Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment

Summary

Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological‐based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.

Introduction

Mitochondria play important roles in cell respiratory processes, metabolism, energy production, intracellular signaling, free radical production, and apoptosis 1, 2. These super dynamic organelles can change their morphology, number and function in reaction to physiological situations, and stressors like hormones, diet, temperature, and exercise 2. Many lines of evidence suggest that mitochondria can critically regulate cell death and survival, play an essential role in aging, and are one of the key features of neurodegeneration 3. In the central nervous system (CNS), sufficient energy supply which required for neuronal survival and excitability is mostly dependent on mitochondrial sources; therefore, brain is much more vulnerable to mitochondrial dysfunction 4. Appropriate function of mitochondria is fundamental for activation of proper stress reactions and maintenance of metabolic homeostasis that have been implicated in life span extension and aging 5. Cellular programs do the task of maintenance of mitochondrial quality and integrity by monitoring and substituting dysfunctional mitochondria with new organelles 6. They necessitate the replication and transcription of mitochondrial protein synthesis, mitochondrial DNA (mtDNA), and separate structural events in the cytoplasm, such as mitochondrial proliferation, mitochondrial autophagy (mitophagy), and mitochondrial fusion/fission 7.

Mutations of mtDNA 8, changed mitochondrial dynamics (mitochondrial fusion/fission, movement, morphology, size, and transport), gene mutations 9, and impaired transcription contribute to mitochondrial dysfunction which results in bioenergetics defects 10. There are several evidences that prove the importance of the mitochondrial dysfunction in the pathogenesis of diseases such as neurodegenerative disorders 3, 11, 12. In addition to this, studies proved that mitochondria have an association with mutated proteins in neurodegenerative diseases 10. Likewise, there is an interaction between mitochondria and a remarkable amount of disease‐specific proteins linked with genetic forms of neurodegenerative diseases. Therefore, treatments targeting at fundamental mitochondrial processes, such as free radical generation or energy metabolism and particular relations of mitochondria with disease‐related proteins, show great potential 3.

Mitochondrial Biology and Dynamics

As dynamic organelles, mitochondria are vital for cellular death, life, and differentiation. These also involve in several functions, such as iron/sulfur cluster, amino acid synthesis, and fatty acid metabolism, 13. While they are best recognized for production of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), they contain numerous other biochemical pathways and also are centers for ion homeostasis 14. Electron and proton transport is partly done by macromolecular protein complexes, whose subunits are encoded by both mitochondrial and nuclear DNA 13. Complexes I and III are process main sites in the mitochondrial respiratory chain (RC) 15. Since its sequencing, 13 proteins encrypted by the mitochondrial genome have been identified and linked to a range of maternally inherited disorders. There are about 1500 mitochondrial proteins encoded by nucleus, although less than half were found with experimental attempts. A molecular framework is provided by a whole inventory of protein for this organelle across tissues for the investigation of mitochondrial pathogenesis and biology 14.

There are two important, opposite forces including mitochondrial fusion and mitochondrial fission which maintain the growth, shape, distribution, and structure of mitochondria 16, 17. The fusion and fission of mitochondria at the organellar level is the primary pathway of quality control (QC), which is vital when the molecular pathways are overpowered 13. Repetitive cycles of mitochondrial fission and fusion machinery regulate the mitochondria morphology and are crucial for mitochondrial dynamics 18. Furthermore, mitochondrial dynamics enable the mitochondrial function maintenance and are involved in a mitochondrial QC system by separation or mixing of contents. Various qualities of stress cause various responses from the mitochondrial fission/fusion machinery: low stress triggers mitochondria fusion, prolonged or high stress favors fission 13. The mitochondrial fission 1 (Fis1) and dynamin‐related protein (Drp1) control and regulate fission. The increase in mitochondrial free radicals activates Fis1, which is critical for mitochondrial fission. In contrast, mitochondrial fusion is controlled by three guanosine triphosphatase (GTPase) proteins: two outer membrane localized proteins mitofusin 1 and 2 (Mfn1 and Mfn2) and an inner membrane localized protein optic atrophy 1 (Opa1) 16 (Figure 1).

Figure 1.

Regulation of mitochondrial quality control by fission and fusion phenomena.

The balance between fusion and fission rates determines the mitochondria lengths and the degree to which they form closed networks. Pathogenic and metabolic conditions within mitochondria and their cellular environment have effects on these rates 17. The disproportion between fusion and fission in the mitochondria brings about functional changes, including increased lipid peroxidation, increased reactive oxygen species (ROS) production, decreased membrane potential, decreased respiration, and lower ATP production 16. The clarification of this network helps understanding the multifaceted biological processes, for example, aging 13. According to the literature, mitochondria's structural changes, including decreased mitochondrial mixing (fusion) and increased mitochondrial fragmentation (fission), are important factors linked with cell death and mitochondrial dysfunction in aging‐related diseases and neurodegenerative diseases 19 (Figure 1).

Mitochondrial fragmentation is the disintegration of one mitochondrion after toxins are applied to the cell and/or when the cell expresses mutant protein(s). This is different from mitochondrial division that is the normal division of a single mitochondrion into two; however, mtDNA synthesis happens in both processes 16. This abnormality and dysfunction of mitochondrial dynamics happens selectively in the most common chronic age‐related and proteopathic neurodegenerative diseases which their manifestation occurred in the brain including Alzheimer's disease (AD) 20, Parkinson's disease (PD) 21, Huntington's disease (HD) 22, and amyotrophic lateral sclerosis (ALS) 23. Early recognition of mitochondrial dysfunction and abnormal mitochondrial dynamics enables us to interfere in disease processes to restrict disease effects and to change disease progression 16.

Recently, it has been shown that there is a link between mitophagy and mitochondrial dynamics in terms of function 24, 25. Furthermore, mitochondrial fusion and fission have significant parts in disease‐related processes, such as mitophagy and apoptosis 17. The segregation of impaired mitochondria due to fission and consequent inhibition of their fusion mechanism is hypothesized to be a requirement for mitophagic degradation 13. Finally, it dysfunctional and damaged mitochondria can be removed from the vital network of mitochondria via mitophagy process. This process is seen as representing a very specific pathway of QC that has significant biological relevance and performs at the organellar level 26. Mitophagy impairments lead to the development of several diseases, such as AD 27, PD 28, HD 29, and ALS 30.

Mitochondrial Dysfunction and Neurodegenerative Diseases

As organelles of eukaryotic cells, mitochondria have several functions, such as synthesis of ATP through energy transduction. On the other hand, ROS are made as by‐products of this process which may damage different types of molecules causing mitochondrial dysfunction. Therefore, mitochondrial activity is a double‐edged sword which can be both potentially dangerous and essential 13. Some mitochondrial abnormalities were recognized in animal and human models with the metabolic syndrome, such as lower mitochondrial mass 31, altered mitochondrial morphology 32, reduced fatty acid oxidation 33, overproduction of ROS 34, and reduced mitochondrial OXPHOS 35, 36. More than 50 diseases are caused by mitochondrial dysfunction: from neonatal fatalities to cancer 37 and type II diabetes 38, and it is also a possible cause of neurodegenerative diseases 14. Literature indicates that atypical mitochondrial functions, such as accumulation of mutations that impair mitochondrial protein synthesis occurred in infant mortalities 39. In addition, mitochondrial decline and mtDNA damage which play crucial roles in the etiology of cancer fall into three main classes: (1) increased accumulation of mtDNA deficiencies, (2) increased mitochondrial oxidative stress and ROS production without ATP depletion, and (3) inhibition of OXPHOS by mtDNA mutations 40. Likewise, type II diabetes has been related to accumulation of mtDNA proteins synthesis mutations, increased accumulation of mtDNA defects, down regulation of mitochondrial function and gene expression, increased mitochondrial ROS production with ATP depletion, and decreased mitochondrial OXPHOS 41. Moreover, multiple line of evidence indicated that impaired calcium influx, dissipation of mitochondrial membrane potential, accumulation of mutant proteins in mitochondria, increased accumulation of mtDNA deficiencies, and deficiencies in mitochondrial OXPHOS are significant cellular changes in late‐onset neurodegenerative diseases 19 (Table 1).

Table 1.

Mitochondrial dysfunction in several diseases

Disease	Mitochondrial abnormalities	Reference
Metabolic syndrome	Reduction in mitochondrial mass	31, 32, 33, 34, 35, 36
	Alteration in mitochondrial morphology
	Decrease in fatty acid oxidation
	Overproduction of ROS
	Reduction in mitochondrial OXPHOS
Neonatal fatalities	Accumulation of mutations	39
	Impairment of mitochondrial protein synthesis
Cancer	Increased accumulation of mtDNA deficiencies	40
	Increased production of mitochondrial oxidative stress
	Increased production of mitochondrial ROS without ATP depletion
	Inhibition of OXPHOS by mtDNA mutations
Type II diabetes	Accumulation of mtDNA proteins synthesis mutations	41
	Increased accumulation of mtDNA defects
	Downregulation of mitochondrial function and gene expression
	Increased production of mitochondrial ROS with ATP depletion
	Reduction in mitochondrial OXPHOS
Neurodegenerative diseases	Impairment of calcium influx	19
	Dissipation of potential mitochondrial membrane
	Accumulation of mutant proteins in mitochondria
	Increased accumulation of mtDNA deficiencies
	Defects of Mitochondrial OXPHOS

As mentioned earlier, the dysfunction of mitochondria is linked to the aging as an onset of numerous diseases and it has tremendous cellular consequences 42. Alterations of mitochondrial activity and number are associated with age‐related diseases such as cancer, diabetes, and neurodegenerative diseases 40. Impaired Ca²⁺ buffering or energy supply, control of apoptosis by mitochondria or increased ROS production can contribute to the progressive decline of long‐lived postmitotic cells, such as neurons 43. Furthermore, mitochondrial ROS generation is known as key factors accountable for cell death and disease progression in age‐dependent diseases 16. Regardless of the main link between human diseases and mitochondrial dysfunction, generally, the molecular causes for dysfunction are poorly understood or even have not been identified 2.

Mitochondria contain multiple electron transporters that can produce a broad network of antioxidant defenses and ROS 44. Mitochondrial insults, including oxidative damage itself, may lead to an imbalance between ROS production and removal, causing net ROS production 45. The significance of aging of net production of mitochondrial ROS is supported by evidence that longevity is increased by improving mitochondrial antioxidant defenses 3. Also, mitochondria is said to play a significant role in neurodegenerative diseases related to aging. Mitochondria are main controllers of cell death, an important characteristic of neurodegeneration. Certainly, aging is the highest risk factor for neurodegenerative diseases, and mitochondria are supposed to speed up aging by the net production of ROS and accumulation of mtDNA mutations. It is hypothesized that somatic mutations of mtDNA developed during aging increase physiological decline that happens with aging and aging‐related neurodegeneration 3.

Generally, neurodegenerative diseases are a heterogeneous group of disorders characterized by gradually progressive, selective loss of physiologically or anatomically related neuronal systems. Prototypical examples of the most common chronic neurodegenerative diseases associated with aging and aggregation of misfolded proteins are AD, PD, HD, and ALS. Regardless of this heterogeneity, mitochondrial contribution is probably an central common theme in these disorders 3. Recently, it was clarified that oxidative damage and mitochondrial dysfunction are main factors in neuronal loss 46. Free radicals, normally created by mitochondrial respiration, result in oxidative impairment of proteins, carbohydrates, nucleic acids, and lipids. Nevertheless, the mechanism of neuronal death due to oxidative damage is not clear 47. Cellular injuries, such as oxidative stress, may damage the capacity of cell to make adequate ATP for homeostasis, eventually resulting in necrosis or apoptosis 7. In several neurological diseases, mitochondrial defects and/or dysfunction in mtDNA are associated with neurodegeneration. There are studies on the role of mitochondria in controlling pathways of apoptotic cell death due to neurodegenerative disease. There is evidence that in brains of patients with neurodegenerative diseases, mitochondria become dysfunctional in tissue by reducing ATP supply and energy production, enhancing generation of ROS, change in calcium buffering, and opening of the mitochondrial permeability transition pore (mPTP) 18.

The majority of ROS production generated in cells by mitochondrial metabolism which implicated in numerous pathological alterations of the CNS including neurodegeneration 48, 49. As mitochondrial metabolism is both principal source of free radicals and high‐energy intermediates, it is proposed that acquired or inherited mitochondrial defects can cause neuronal degeneration due to oxidative damage and energy defects. Dysfunction of mitochondrial respiratory chain was reported related to primary mtDNA abnormalities, and in nuclear genes mutations that are directly involved in mitochondrial functions, including paraplegin, surfeit locus protein 1 (SURF1), and frataxin. Increased production of free radical and OXPHOS defects have also been seen in diseases that are not caused by primary abnormalities of mitochondria. The mitochondrial dysfunction in these cases can be an epiphenomenon that could be essential in precipitating a cascade of events causing cell death. Understanding the mitochondria role in the pathogenesis of neurodegenerative diseases can be important for the development of therapeutic strategies in these disorders 50. Increasing evidence reveals a dominant fundamental role of mitochondrial dysfunction in the neurodegenerative disorders’ pathogenesis, including AD, PD, HD, and ALS 1, 10, 16, 19 (Table 2).

Table 2.

Main causes of the mitochondrial dysfunction in the most common neurodegenerative diseases

Disease	Abnormalities result in mitochondrial dysfunction	Reference
AD	Deposition of Aβ within mitochondria in the brain of patients with AD	51, 52, 53, 54
	Impairment of mitochondrial OXPHOS in the brain of patients with AD
	Downregulation of PGC‐1 in the brain of patients with AD
	Modulation of Aβ aggregation cascade through PPAR‐γ dysregulation
PD	Significant reduction in ATP in the putamen and midbrain	21, 55, 56, 57, 58
	Significant reduction in PCr in the putamen
	Enhanced formation of free radicals
	Induction of permeability transition
	Impairment of intracellular calcium homeostasis
	Induction of Oxidative Stress
	Downregulation of PGC‐1 in the brain of patients with PD
	Development of neurodegeneration through PPAR‐γ dysregulation
HD	Impairment of mitochondrial function by mHtt	59, 60, 61, 62, 63
	Downregulation of PGC‐1 and its downstream genes
	Suppression of PPAR‐γ activity by recruitment into Htt aggregates
ALS	Decrease in mitochondrial Ca2+ capacity	64, 65, 66, 67, 68
	Alteration of axonal mitochondria distribution
	Alteration in mitochondrial morphology
	Enhanced production of mitochondrial ROS
	Defects of mitochondrial respiration in the CNS and muscles of patients with ALS
	Defects of ATP production in the CNS and muscles of patients with ALS
	Reduction in mtDNA copy number
	Deficiencies in activity of respiratory chain
	Downregulation of PGC‐1 and its downstream genes
	Increases in several miRNAs involved in neuromuscular junction and skeletal muscle regeneration
	Development of neuroinflammation as a ALS hallmark, through PPAR‐γ dysregulation

Mitochondrial Complexes and Neurodegenerative Diseases

Mitochondria are complex organelles whose dysfunction causes a broad range of diseases 14. Several studies illustrated that deletions or mutations of single complex subunits, including complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (ubiquinol cytochrome C oxidoreductase), complex IV (cytochrome C oxidase), and complex V (ATP synthase) 69 might have an important effect on the entire complex formation and highlighted the significance of genome coordination for appropriate complex function and assembly 42. Mitochondrial functions are changed in brains of individuals with certain neurodegenerative disorders 70, 71. Dysfunction of mitochondrial electron transport chain (ETC.) complexes has been associated with the pathogenesis of the most common chronic age‐related neurodegenerative diseases which associated with misfolding protein aggregation including AD, PD, HD, and ALS 47, 72, 73. It is highlighted that the accumulation of mutant aggregate‐prone proteins induced by proteasomal inhibition results in impairment of the mitochondrial respiratory chain complexes activity. In addition, mitochondrial complex deficiencies have an essential role in pathogenesis of AD 74, PD 75, HD 71, and ALS 76 (Figure 2).

Figure 2.

Mitochondrial complex defects in pathogenesis of AD, PD, HD, and ALS.

Impairment of the mitochondrial respiratory chain complexes activity in AD (mitochondrial complex I, III, and IV deficiency), PD (mitochondrial complex I and IV deficiency), HD (mitochondrial complex II, III, and IV deficiency), and ALS, respectively (mitochondrial complex I, II, III, and IV deficiency). The combined mitochondrial complex deficiencies caused by increase in the expression of hyperphosphorylated tau and Aβ plaques, mα‐synuclein, mHtt, and mSOD1 result in promoting the accumulation of aggregated/misfolded of these proteins via the proteasome activity inhibition in patients with AD, PD, HD, and ALS, respectively.

Mitochondrial respiratory chain complex I catalyzes transfer of electron from NADH to the ubiquinone pool (Q), with concurrent vectorial pumping of proton through the inner mitochondrial membrane 77. This complex is one of the main sites in which electrons are released and react with oxygen, resulting in ROS production, thus causing oxidative stress 78. Complex I deficiency is among the most frequent reasons of mitochondrial disease in humans 79. Mitochondrial respiratory chain complex II is an essential component of both the Krebs cycle as well as the mitochondrial respiratory chain, which play a critical role for generating ATP 80. This is the only one of the mitochondrial respiratory chain complexes that is completely encoded by nuclear genes. In complex II, additional electrons from succinate are transferred into the Q 81. The production or triggering of ROS by the mitochondrial complex II may have either deleterious or beneficial effects based on the (patho)physiological situation. An enhanced production of mitochondrial ROS is related to multiple pathophysiological disorders, such as neurodegenerative diseases 82. Mitochondrial respiratory chain complex III channels electrons from the Q to cytochrome c, simultaneously pumping protons from mitochondrial matrix space into the intermembrane space 83. Complex III deficit is a fairly common deficiency of the OXPHOS system, linked with a broad range of neurological disorders 84. Mitochondrial respiratory chain complex IV or cytochrome c oxidase (COX) is the terminal complex of the electron transport chain. It catalyzes the electron transfer from cytochrome c to reduce molecular oxygen (O₂) and form two molecules of water in a reaction that is coupled to proton pumping across the inner mitochondrial membrane. Complex IV deficiencies result in several human clinical phenotypes, with unclear molecular mechanism 85. Mitochondrial respiratory chain complex V is the fifth enzyme of the OXPHOS system located in the mitochondrial inner membrane 86. In the mitochondrial matrix, it synthesizes ATP from adenosine diphosphate (ADP) using energy provided by the proton electrochemical gradient 87. Most individuals with complex V deficit had clinical onset in the neonatal period with multiorgan failure or severe brain damage leading to a high mortality, such as cardiomyopathy and neuromuscular disorders 86.

Mitochondrial Biogenesis and Neurodegenerative Diseases

Mitochondrial biogenesis assumes a critical part to keep mitochondrial homeostasis during the mitochondria life cycle and finally meet the physiological demands of eukaryotic cells 20. It is proposed that sequential loss of mtDNA amount in long‐term focal cerebral ischemia points to the failure of mitochondrial renewal mechanisms. Moreover, strong research evidence recommends a probable reduction in ROS production by the biogenesis of a significant density of functional mitochondria 88. As a highly regulated process, mitochondrial biogenesis requires the participation of both the mitochondrial and nuclear genomes and happens frequently in healthy cells that continually divide and fuse with each other, while in unhealthy cells, division (fission) is leading and after cerebral insults, the mitochondrial network fragments 18. Increased biogenesis is compatible with the mtDNA copy number and enhanced mitochondrial gene expression. The gene expression profile associated with mitochondrial biogenesis includes peroxisome proliferator‐activated receptor‐γ coactivator 1 alpha (PGC‐1α), mitochondrial transcription factor A (TFAM), nuclear respiratory factor 1 and 2 (NRF1 and NRF2), and mitochondrial transcription factor B1 (TFB1M), 89.

As mitochondria are not synthesized from the beginning, they should proliferate from the ones already existing to keep biogenesis 6. Their biogenesis appears to be controlled via several processes, including (1) synthesis of outer and inner mitochondrial membranes, (2) synthesis of mitochondrial proteins, (3) synthesis and import of proteins encoded by the nuclear genome, (4) lipid import, (5) oxidative phosphorylation, (6) replication of mtDNA, and (7) mitochondrial fusion and fission 6, 90. Usually, alterations in physiological state including enhanced rates of ATP consumption activate mitochondrial biogenesis for approaching the existing cells capacity to generate it. Some of the main triggers of mitochondrial biogenesis include cell division and repair, embryonic development, alterations in physiological state such as sympathetic stimulation, calorie restriction, exercise, cold stress, energy limitation, hormones (thyroid hormone, leptin, and erythropoietin), and mitochondrial disease/damage such as inflammation, hypoxia/ischemia, and oxidative/nitrosative stress 7. Mitochondrial damage is reflected by mtDNA impairment and by a decrease in mitochondrial function, mitochondrial RNA (mtRNA) transcripts, and protein synthesis 18.

Multiple investigations offer that disruption of mitochondrial function considered as a critical cause in the pathophysiology of numerous neurological disorders, and adaptive mitochondrial biogenesis has been studied in the nervous system 91. Reduced mtDNA/nDNA ratio also shows a decreased mitochondrial biogenesis. It is highlighted that impaired mitochondrial biogenesis potentially contributes to the mitochondrial dysfunction and has a significant role in the pathogenesis of the neurodegenerative diseases. Likewise, it should be noted that genes encoding proteins which play a key role in mitochondrial biogenesis are linked with those diseases 20. Taken together, induction or improvement of mitochondrial biogenesis may be considered as a novel therapeutic target and confirm a modern neuroprotective approach for most of diseases such as neurodegenerative diseases including AD, PD, HD, and ALS in the near future 92 (Figure 3).

Figure 3.

Mitochondrial biogenesis as a novel therapeutic target in treatment of AD, PD, HD, and ALS.

Mitochondrial biogenesis as a potential therapeutic approach may use to induce neuroprotection through alleviation of the mitochondrial complexes deficiencies that induced by the expression of hyperphosphorylated tau and Aβ plaques, mα‐synuclein, mHtt, and mSOD1 in AD, PD, HD, and ALS, respectively. This neuroprotective strategy results in promoting the degradation of aggregated/misfolded of these proteins via the proteasome activity induction.

Transcriptional Approaches to Improve Mitochondrial Function

There are limited number of studies on neuronal mitochondrial biogenesis, but research on other tissues and model systems shows a series of signal transduction proteins, transcription factors, and transcription co‐activators should play their crucial roles to regulate mitochondrial mass and number inside neurons 43. Maintaining effective metabolic output is essentially dependent on regulation of the complex protein‐folding environment inside the organelle. Dysregulation of protein homeostasis happens over time via stress induced by the accumulation of ROS and mutations in the mitochondrial genome introduced during replication 42. Major challenges in cell biology are recognizing all the proteins in this organelle and understanding how they involved in pathways 14. The dynamics of mitochondrial function and biogenesis is a complex interplay of cellular and molecular processes that ultimately shape bioenergetics capacity. Mitochondrial mass, by itself, represents the net balance between rates of biogenesis and degradation 93.

Mitochondrial biogenesis is dependent on different signaling cascades and transcriptional complexes that promote the formation and assembly of mitochondria. It is a process that is heavily dependent on timely and coordinated transcriptional control of genes encoding for mitochondrial proteins 93. Biogenesis of mitochondria is regulated mostly at the transcription level, and several nuclear‐encoded mitochondrial genes should be expressed in coordination with the 13 mitochondrial‐encoded genes. This synchronized bigenomic program comprises of nuclear‐encoded mitochondrial proteins that regulate mtDNA replication as well as transcription and also necessitates the induction of mitochondrial DNA polymerase (Polγ), TFAM, and mitochondrial transcription factor B2 (TFB2M) 94, 95. Also, the nuclear regulation mechanisms cause the tissue induction and signal specific subsets of genes that serve particular functions. Most of the mitochondrial proteome is assigned to lineage‐specific proteins; therefore, the transcriptional program corresponds to the cell's mitochondrial phenotype and mass to the functions of each tissue and the physiological energy requirements 7.

PGC‐1 family members (e.g., PGC‐1α and PGC‐1β) coactivate genes encoding proteins for transcription and replication of mtDNA as well as importation of mitochondrial protein 7, 94, 96, 97. They also have contribution in the physiological integration of mitochondrial biogenesis with oxidative metabolism and provide overlapping and amplifying regulation of several nuclear‐encoded mitochondrial genes 98. As a co‐transcriptional regulation factor, the PGC‐1α provokes mitochondrial biogenesis by activating several transcription factors, including NRF1 and NRF2. Furthermore, it is called GA‐binding protein A (GABPA) that regulates the expression of multiple nuclear genes to encode mitochondrial proteins such as TFAM. The TFAM contributes to the mtDNA maintenance and motivates the replication and transcription of mtDNA as well as PPARs 18, 94, 99.

As a transcriptional coactivator, PGC‐1 functions together with combination of other transcription factors such as peroxisome proliferator‐activated receptors (PPARs) in the regulation of mitochondrial biogenesis. PPARs, in particular PPAR‐γ, may be a major signaling pathway involved in neuroinflammation 68. PPAR‐γ as a ligand‐activated transcriptional factor is a member of the nuclear hormone receptor superfamily. It has effect on the activity or expression of numerous genes in a range of signaling networks, including insulin sensitivity regulation, cell fates, immune responses, fatty acid oxidation, glucose homeostasis, cardiovascular integrity, and redox balance 100. Likewise, PPAR‐γ is known as a main regulatory factor in the target genes modulation with PPAR response element (PPRE) in their promoters, such as those encoding for oxidative stress, inflammation (COX‐2), inducible nitric oxide synthase (iNOS), and nuclear factor‐kappaB (NF‐κB), and apoptosis 68.

In addition, the threonine/serine AMP‐activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that is activated as a consequence of reflecting low energy reserve 101, 102. It stops the continuous progress of ATP‐consuming reactions and triggers ATP‐generating pathways 103. AMPK activation results in modulations of several factors like PGC‐1α, to produce ATP, while simultaneously stop energy consumption 104. It is indicated that AMPK activation appears to be essential in the mitochondrial biogenesis 105 through regulating PGC‐1α directly 106 or even indirectly by modulating sirtuin 1 (SIRT1) activity 101. It also inhibits the growth‐controlling mammalian target of rapamycin (mTOR) pathway 107, 108 by phosphorylation of the tuberous sclerosis 2 (TSC2) tumor suppressor together with the tuberous sclerosis 1 (TSC1) 108. Activation of the mTOR indicating by Akt/PKB includes the phosphorylation and inactivation of TSC2 7. Moreover, Akt/PKB induces mitochondrial biogenesis via the cyclic AMP response element‐binding protein (CREB1) and NRF1 phosphorylation, thus allowing target gene activation and nuclear translocation 109.

Mitochondrial biogenesis involves other transcription factors such as sirtuins. Sirtuins (SIRTs) are a family of the nicotinamide adenine dinucleotide (NAD+)‐dependent protein deacetylases which contribute in numerous cellular processes such as cell cycle, transcription, energy metabolism, mitochondrial functions, aging, apoptosis, and cell survival 104, 110, 111. There are seven sirtuins for mammalian with different activities which localized to the nucleus (SIRT1, SIRT6, SIRT7), cytosol (SIRT2), and mitochondria (SIRT3, SIRT4, and SIRT5) 111. There are several evidence to suggest that sirtuins as the transcriptional regulators may have potential therapeutic effects on a several chronic age‐related and aggregate‐forming neurodegenerative diseases including AD, PD, HD, and ALS. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity 110, 111, 112. It is indicated that SIRT1 induces mitochondrial biogenesis by activating the master regulator PGC‐1α 43. Furthermore, SIRT3 which interacts with mitochondrial complex I is another novel therapeutic target for neurodegenerative diseases 104. SIRT3 as a downstream target gene of PGC‐1α mediates downregulation of the PGC‐1α‐dependent intracellular ROS production and stimulates mitochondrial biogenesis 113.

There are also many other transcription factors including orphan nuclear estrogen‐related receptors (ERRs) which expressed by aerobic tissues. For instance, the estrogen‐related receptor alpha (ERRα) is a PGC‐1α companion in the genes expression essential for fatty acid β‐oxidation 114, 115. Along with CREB1, the Ying–Yang 1 (YY1) transcriptional initiator element‐binding protein plays a part in the constitutive expression of respiratory and other energy metabolism genes 116, 117. The myocyte‐specific enhancer factor 2A (MEF2A) and the nuclear‐encoded proto‐oncogene c‐Myc are other important genes for mitochondrial biogenesis 118; these are, respectively, activator of PGC‐1β and vital regulator of oxidative capacity in cardiac and skeletal muscle activated by NRF1 119. Moreover, MEF2A contributes to activation of stress‐induced genes and growth factor and also promotes cell survival as well as cell growth 119.

On the other hand, considerable development has been made in expanding mitochondria‐targeted antioxidants, as dysregulation of protein homeostasis induced by the accumulation of ROS and mutations in the mitochondrial genome. Antioxidants protect neurons against mitochondrial functional and structural abnormalities, oxidative damage, and mutant proteins 120. In the last decade, several antioxidants have been developed such as mitoquinone (MitoQ) as the triphenylphosphonium‐based antioxidant as well as Szeto‐Schiller 31 and 20 peptides (SS31 and SS20 peptides) as the small peptide‐based antioxidants which bind to the inner mitochondrial membrane 120, 121, 122.

MitoQ is a form of coenzyme Q which considered as a potential therapeutic antioxidant to protect against mitochondrial oxidative damage by reducing free radicals such as ROS 123 and lead to the neuroprotection against age‐related mitochondrial insults 124. Dumont and his colleagues indicated that MitoQ therapy reduces β‐amyloid plaque number and area, amyloid beta‐42 (Aβ‐42) levels, and brain oxidative stress, as well as improves cognition in a transgenic mouse model of AD 125. Furthermore, it was found that the combination of creatine and MitoQ shows potential neuroprotective impacts on the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) model of PD 126. In addition, administration of MitoQ could extend cell survival and ameliorate motor performance and brain atrophy in a transgenic mouse model of HD 127. Also, Miquel and his colleagues found modest neuroprotective effects of MitoQ in a mouse model of ALS 128.

Likewise, SS31 and SS20 antioxidant peptides represent a novel therapeutic approach that can scavenge mitochondrial free radicals including ROS and results in inhibition of mitochondrial permeability transition and cytochrome c release which prevents oxidant‐induced cell death 104, 129, 130. Recently, preclinical studies support potential use of the mitochondria‐targeted antioxidants as an effective treatment for neurodegenerative disorders 131. Manczak and her colleagues stated that SS31 prevents Aβ toxicity as well as decreases learning and memory deficits and may consider as a potential treatment for AD 132. Moreover, SS31 and SS20 demonstrated significant neuroprotective effects on dopaminergic neurons of MPTP‐treated mice 133. Likewise, SS31 may use for HD therapy by promoting mitochondrial function and neuronal viability 134. Additionally, SS31 is a novel therapeutic approach to treat neuronal damage induced by oxidative stress in a mouse model of ALS. It targets the ROS production at the inner mitochondrial membrane and prevents further mitochondrial damage 122.

AD

AD is the most common neurodegenerative disorder marked by progressive loss of memory, characterized by the increased presence of extraneuronal amyloid plaques derived from the proteolytic processing of the amyloid precursor protein (APP) and intraneuronal neurofibrillary tangles (NFTs) made from hyperphosphorylated tau protein (pTau) in the brain. Plaques comprise amyloid beta (Aβ) fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of AD 135, 136, 137. Recent evidence indicates that mitochondrial dysfunction is a noticeable and early feature of AD with lower energy metabolism as one of the best known primary abnormalities in this disease 20. They state that intervention at the mitochondrial level could improve Aβ triggered degeneration and dysfunction. This is proved by the in vivo evidence of Aβ accumulation inside mitochondria in the brain of patients with AD 51, 52. A plenty of evidence declare that levels of mitochondrial Aβ are related to the degree of cognitive impairment as well as the extent of mitochondrial dysfunction in different regions of brain in AD 51, 52, 138. Deposition of Aβ1–40/1–42 in AD cybrids can raise likelihood of mitochondrial dysfunction as well as cell death 51, but the mechanism of Aβ‐mediated mitochondrial dysfunction possibly causing neuronal disorder is not exactly clear yet 52. Additionally, the mitochondrial OXPHOS impairment has been described in the brain of patients with AD by Hauptmann and his colleagues 52. Interestingly, several researches have shown that PGC‐1α as a transcriptional coactivator serves as a regulator of Aβ generation because it affects β‐secretase (BACE1) degradation. PGC‐1α has been shown to play a significant role in energy metabolism by controlling mitochondrial function in several tissues. The PGC‐1 expression considerably reduced in the brain of patients with AD and was involved in the pathological generation of Aβ by influencing the processing of APP; in part by increasing the α‐secretase activity 53. Furthermore, Camacho and his colleagues stated that PPAR‐γ can be contributing to the modulation of Aβ aggregation cascade leading to neurodegeneration in Alzheimer's disease 54 (Table 2).

Multiple documents recommended that mitochondrial dysfunction, particularly, deficiencies in mitochondrial respiratory chain complex I has been considered a potential unifying factor in pathogenesis of the neurodegenerative disorders including AD 56, 139, 140. Moreover, intracellular NFTs comprised of hyperphosphorylated tau protein as well as extracellular Aβ plaques represent the major hallmarks of AD. Hyperphosphorylated forms of tau selectively impair complex I, lead to increased ROS levels, and result in reduced levels of ATP 141, 142, 143. Clinical and experimental observations suggest that complex I inhibition could contribute to pathogenic mechanisms in some sporadic tauopathies 74 (Figure 2). Furthermore, reduced activity of mitochondrial enzymes, such as complex III, has been reported. Similarly, the mitochondrial complex IV activity is decreased by 70% in patients with AD, which is related to the excitotoxic cell death. It has been stated that a reduction in complex IV activity in the brain associated with aging 72 (Figure 2).

Likewise, it is believed that glutamate excitotoxicity happens in chronic neurodegenerative diseases such as AD 47, 72, 73. Insufficient control over glutamate release as a result of mitochondrial complex IV and III deficiency can lead to neuronal cell death. Glutamate release happens mainly through reversal of glutamate transporters of plasma membrane during severe energy stress. Reduction in intracellular ATP leads to depolarization of Ca²⁺ and plasma membrane in glutamate release of from the cytoplasmic pool 72. The accumulation of mtDNA mutations could be at the origin of ETC. malfunction 3, 144. Moreover, Costa and his colleagues showed that mitochondrial dysfunction has effect on the stress response of endoplasmic reticulum (ER) activated by Aβ peptide (Aβ1–40 isoform) 51, 52. Postmortem research on the AD brain showed that activity of complex IV decreased by 52% in the hippocampus, by 37% in the temporal cortex, and by 27% in the cerebral cortex 72.

The status of this vital feature of mitochondrial function and life in AD is not clear 20, 43. While increased mtDNA, ETC. gene expression and ETC. protein were seen in AD brain 43, 145, other studies alternatively indicate a reduction in those in brain of patients with AD 43, 146. Upregulated ETC. genes expression happens in mutant APP transgenic mice and decreased Aβ levels induce mitochondrial biogenesis 147. Possibly, in different stages of disease, neurons exhibit different forms of mitochondrial biogenesis 148. It was indicated that Aβ oligomers induce oxidative stress and mitochondria dysfunction, which provoke tau protein hyperphosphorylation and NFTs formation. These events close in on tau protein aggregation and autophagic dysfunction and then lead to neurodegeneration and cell death in AD 149 (Figure 4). Moreover, it was mentioned that expression levels of genes encoding proteins involved in mitochondrial biogenesis such as PGC‐1α, NRF1, NRF2, and TFAM have been associated with the neurodegenerative diseases like AD 20. Expression levels of these genes significantly reduced in both AD hippocampal cells and tissues, proposing a decreased mitochondrial biogenesis 20. Nevertheless, considering the pleiotropic roles of PGC‐1α, it is not clear yet how mitochondrial biogenesis signaling is changed and whether such changes have a hand in mitochondrial dysfunction in AD 20.

Figure 4.

Limitation of the pathological progression, neurodegeneration, and cell death in AD through increasing the PGC‐1α activity as a key regulator of the mitochondrial biogenesis.

Additionally, TFAM plays an important role in the maintenance of mtDNA integrity 150. It locates on chromosome 10, on which many genes have been reported to be associated with sporadic AD 151. The moderate likely risk of AD related to TFAM haplotype and genotypes was found 152. Also in Caucasians, mutations in TFAM contributed to the pathogenesis of sporadic late‐onset AD 150. Moreover, the stimulation of PPAR‐γ reduces inflammation in neurological disorders with an inflammatory element such as AD 54. Recent evidence indicates that PPAR‐γ activation modulates Aβ production in cellular models relevant to AD. It shows that PPAR‐γ agonists downregulate deposition of Aβ that happens in AD, while its mechanism is still controversial 153. Together with this fact, it is hopefully predicted that PPAR‐γ may apply as a drug target for the management of neurological disorders like AD 54. Furthermore, inducing mitochondrial biogenesis by AMPK activation considered as a therapeutic target for AD 154. In addition, activation of SIRT1 in brain protects against learning impairments and hippocampal degeneration by decreasing the acetylation of the SIRT1 substrates such as PGC‐1α which results in PGC‐1α activation and also reduction in amyloid pathology in a mouse model of AD 155. Overall, this data demonstrated mitochondrial biogenesis induction decreases mitochondria dysfunction. Based on data mentioned above, the impaired mitochondrial biogenesis has been suggested as underlying factor in mitochondrial dysfunction in AD and increasing mitochondrial biogenesis may represent a possible pharmacologic strategies for the AD treatment 20.

PD

PD is a progressive neurological movement disorder linked to uncertain etiology having possible effects of genetic‐environmental factors 156. However, the cellular mechanisms that result in cell death in the nigrostriatal system in PD are still unclear 157, 158, it is generally accepted that the causes of PD are mainly mitochondrial dysfunction, oxidative stress, chronic inflammation, aberrant protein folding, and abnormal protein aggregation 89, 159, 160. The significant reduction in ATP and phosphocreatine (PCr) in the putamen and the significant reduction in ATP in the midbrain as high energy metabolites are indicative of mitochondrial dysfunction in the mesostriatal dopaminergic neurons in early and advanced PD 21; however, reduction in the ATP production is not just the outcome of mitochondrial dysfunction. In addition, there are other potentially deleterious events such as enhanced formation of free radicals, induction of permeability transition, impaired intracellular calcium homeostasis, and oxidative stress, which in predispose affected cells to necrosis or apoptosis depending on the rate of consumption and depletion of ATP 55, 56. Prohibition of mitochondrial respiratory chain may result in incomplete consumption of O2, decreased of ATP, and increased free radical formation. Free radicals directly inhibit the respiratory chain of mitochondria, which can cause a detrimental cycle that results in oxidative cell damage 161. Several mutations in mitochondrial proteins encoded by nuclear and mitochondrial genes were linked with idiopathic and familial types of PD 71. A genomewide examination of controls and patients with PD showed that expression of PGC‐1α as a master controller of mitochondrial biogenesis was decreased in patients with PD 57 and this can confirm vital roles of mitochondrial dysfunction in the PD pathogenesis. Moreover, dysregulation of PPAR‐γ is linked to the development of neurodegenerative diseases with an inflammatory component‐like PD 58 (Table 2).

In this regard, several postmortem studies have shown a meaningful decline in the mitochondrial complex I activity as well as coenzyme Q10, ubiquinone, and also complex IV in the substantia nigra of PD brains 162, 163, 164 (Figure 2). Complex I deficit is the most common cause of rare diseases of respiratory chain 14 as well as endogenous and environmental oxidative stressors underlying mitochondrial dysfunction observed in neurodegenerative diseases including PD 89, 164. The latest study revealed that activity of complex I is decreased in postmortem brain tissue of patients with PD as a consequence of oxidative damage that leads to instability and loss through degradation of at least one subunit 164. Particularly, loss of activity of complex I at the mitochondrial ETC. has been observed in idiopathic PD 165. Activity of complex I is decreased in the substantia nigra of patients with PD, which may encourage the accumulation of protein inclusions (Lewy bodies) containing α‐synuclein (α‐syn) 166, 167.

Moreover, complex I inhibitors including neurotoxins, such as MPTP which transformed to 1‐methyl‐4‐phenylpyridinium (MPP⁺) and 6‐hydroxydopamine (6‐OHDA), and also pesticides, like rotenone and paraquat cause neuropathological changes similar to PD. Studies on postmortem brains of patients with PD suggested that not only levels of numerous mitochondrial proteins are changed, but also genetic mutations happen in familial PD‐linked genes which may alter mitochondrial function 166. There is evidence that mitochondrial dysfunction is a main PD initiator, because it has been reported that complex I inhibition results in the formation of α‐syn positive cytoplasmic inclusions in cellular and animal PD models 168. As the α‐syn overexpression causes parkinsonism together with the nigrostriatal pathway degeneration, the complex I dysfunction is the most probable cause of PD by modulating the accumulation of misfolded proteins, perhaps via the proteasome inhibition 75, 169 (Figure 2). In animal models of PD (e.g., rodents and primates), for example, administration of complex I inhibitors can replicate several key features of sporadic PD, comprising of selective degeneration of dopaminergic neurons in substantia nigra, aggregation and overproduction of α‐syn, accumulation of Lewy body‐like intraneuronal inclusions, increase in ROS generation, and impairment of behavioral function, which results in irreversible parkinsonism 42, 170.

Several lines of evidence represent that the deficit in PD is at or above the level of PGC‐1α expression, which in turn regulates function of complex I mitochondrial ETC. 171. Lately, varied proteins involved in familial PD, including α‐syn, parkin, PTEN‐induced putative kinase 1 (PINK1), protein deglycase DJ‐1 (parkinson disease protein 7), and leucine‐rich repeat kinase 2 (LRRK2 or dardarin), have been associated with quality control and regulating mitochondrial dynamics 172, 173. In cellular disease models, PGC‐1α activation leads to higher expression of nuclear‐encoded subunits of the mitochondrial respiratory chain and stops the dopaminergic neuron loss induced by the pesticide rotenone or mutant α‐syn 174. Interestingly, parkin and PINK1 have been implicated in regulating mitochondrial biogenesis 175. Parkin has a part in mitochondrial biogenesis 176, 177 by controlling both replication and transcription of mtDNA in proliferating cells. It increases mitochondrial replication, expressions, and transcription of respiratory chain complexes 177. Degradation of parkin‐interacting substrate (PARIS) by parkin raises expression of PGC‐1α‐dependent genes and biogenesis of mitochondria 178. In a neurotoxin mouse model of PD, PGC‐1α overexpression in neurons was protective 57. Consequently, loss of parkin function blocks mitochondrial biogenesis via PARIS accumulation 179. On the other hand, PINK1 is processed by healthy mitochondria and released to trigger neuron differentiation 180. It is thought to facilitate the binding of parkin protein into depolarized mitochondria to induce mitophagy/autophagy and protect cells from stress‐induced mitochondrial dysfunction 181, 182. Gegg and his colleagues reported a vital role of PINK1 in maintaining mitochondrial ETC. activity as well as mitochondrial biogenesis. They showed their dysfunction was involved in sporadic types of PD. Thus, PINK1 expression loss led to reduced levels of mtDNA, mitochondrial biogenesis and mtDNA synthesis 183. Likewise, the mitochondrial protein DJ‐1, as an antioxidant which plays a role in the maintenance of the complex I activity, has been reported to stabilize Nrf2 184, but mutations in DJ‐1 associated with enhancement of the α‐syn aggregation, oxidative stress, and possibly cellular apoptosis 185. In addition, mutation of LRRK2 may result in abnormal phosphorylation of mitochondrial proteins which induces apoptotic cell death 185 (Figure 5).

Figure 5.

Limitation of the pathological progression, neurodegeneration, and cell death in PD through increasing the PGC‐1α activity as a key regulator of the mitochondrial biogenesis.

Moreover, there is an association between TFAM and parkin. As mitochondrial import of parkin was increased in the presence of mitochondrial extract or TFAM, some proteins including TFAM have a part in the export and/or the import of parkin 177. TFAM–parkin complex associated with PD pathogenesis bound to mtDNA control area and enhanced mitochondrial biogenesis 177, 186. Additionally, involvement of TFAM as a multifunctional mtDNA metabolism regulator in pathogenesis of PD (in vitro and in vivo models of PD) directly and indirectly confirmed via increase in mitochondrial respiratory functions and protection from oxidative stress 186. It is also stated that gene therapy based on transfection of mtDNA‐complexed TFAM or recombinant TFAM to cybrid cells of PD led to noticeable improvement of different mitochondrial functions 186, 187. Furthermore, recent investigations have described a new role for PPAR‐γ receptors in the regulation of inflammation 188. Regarding with these reports, PPAR‐γ agonists have been shown to attenuate inflammatory responses in brain as well as animal models of neurodegenerative diseases such as PD which is associated with a considerable degree of neuroinflammation 189. Recently, the antiinflammatory role of PPAR‐γ agonists in mouse models of PD measured by reductions in both microgliosis and astrogliosis. Thus, PPAR‐γ may be beneficial for treating the brain disorders with an inflammatory component‐like PD 190. Likewise, it has been suggested that AMPK activation as a therapeutic approach may promote neuroprotection in PD by mediating mitochondrial biogenesis 191. Moreover, a recent article shown that activation of SIRT1 induces neuroprotection against α‐syn aggregation by activating PGC‐1α as well as molecular chaperones in mice model of PD 192. Indeed, the pathway of mitochondrial biogenesis has come as a possible healing target for PD.

HD

HD is an inherited and an autosomal dominant disorder characterized by psychiatric disturbances, cognitive deterioration, and motor impairment. HD as a fetal neurodegenerative disease caused by the development of cytosine–adenine–guanine (CAG, translated into glutamine) triplet repeats in the huntingtin (Htt) gene (also called HD) and characterized by accumulation of insoluble polyglutamine‐containing Htt protein aggregated in affected neurons 71, 193, 194. Mitochondrial dysfunction is strongly associated with the pathogenesis of HD 195, 196, 197. Cui and his colleagues reported that genetic elimination of PGC‐1α increases HD progression, as measured by the observing striatal neurodegeneration and motor coordination 62, which pinpoints the vital contribution of PGC‐1α in HD 196. Also, it was found that PGC‐1α as a key factor involved in the regulation of multiple pathways such as mitochondrial biogenesis and OXPHOS is downregulated in HD 61, 62. Thus, it was suggested that a deficiency in PGC‐1α and downstream genes may lead to mitochondrial dysfunction in HD, including muscle 198, fat tissue 199, as well as brain 200. Likewise, several downstream targets of PGC‐1α such as NRF1 and NRF2, and TFAM can increase the HD mitochondrial dysfunction 201. Also, several studies revealed that mutant huntingtin (mHtt) impaired mitochondrial functions in mHtt‐expressing striatal cells 59, 60. In turn, mHtt expression suppresses the PPAR‐γ transcriptional activity, which is important for mitochondrial stabilization 63. Decrease in the available PPAR‐γ protein by recruitment into Htt masses results in mitochondrial dysfunction 61, 195, 196 (Table 2).

Additionally, it has been indicated that mitochondrial ATP levels and ETC. activity are reduced in patients with HD 166. In late‐stage patients with HD, decreased activity of several OXPHOS components, including mitochondrial complexes II, III, and IV, has been reported through biochemical research on mitochondria in striatal neurons 202. Further, in research on knock‐in and HD transgenic mice as well as experimental models of HD rodent, reductions of enzyme activities of complexes I, II, III, and IV were seen in brain tissues 203, suggesting that mitochondria contribute to HD pathogenesis 202. In addition, significant declines of mitochondrial activities in complex I, II, III, and IV have been reported in the neostriatum of HD patients’ brains 202, 204 (Figure 2). Decreases of complex II/III activity happen in the brain areas affected by the HD pathogenesis; reduced complex II/III activity in the putamen (by 67%) and caudate (by 29%) was seen in postmortem brain tissue, and activity of complex IV was decreased in both regions by 62% and 30%, respectively 72, 205. The activities of mitochondrial complex III and IV are linked with excitotoxic cell death and reduced by 30% in this disorder 72.

Another potential cause of mitochondrial dysfunction in HD brains is the toxic effects of mutant Htt that result in those changes in mitochondrial complex activities 71. In the postmortem on patients with HD, the main hypothesis behind abnormalities in the mitochondrial respiratory chain reveals that they are indirectly or directly caused by the toxic mHtt expression 59, 148. On one hand, mHtt produces HD‐like symptoms by interrupt complex II activity and mitochondrial Ca²⁺ buffering 206. On the other hand, expression of mHtt selectively damages the complex III activity and promotes the accumulation of aggregated/misfolded Htt proteins via the proteasome activity inhibition in patients with HD (Figure 2). The presence of such feedback systems, containing mitochondrial complex III, proteasome, and misfolded/aggregated Htt proteins suggests that increasing the mitochondrial respiratory, particularly, activity of complex III, can slow down or even prevent the HD progression 71, 202. A clue clarifying the impacts of complex III inhibitors on the Htt aggregates was taken from the evidence that only complex III inhibitors damaged chymotrypsin‐like activity of proteasomes in a ROS‐independent manner. Complex III inhibitors selectively promoted the accumulation of Htt aggregates. As other respiratory inhibitors had no considerable effect on the formation of Htt aggregates, the depletion of ATP does not simply explain the effects of complex III inhibitors 71, 202.

There are several documents about the PGC‐1α role in mitochondrial impairment in HD and its potential as a therapeutic target to treat HD 207. Over the past few years, studies have shown an impaired function of PGC‐1α as a causing of the mitochondrial dysfunction in HD 207. Impaired PGC‐1α levels and function happen in transgenic mice and mouse HD models, striatal cell lines, and also in postmortem brain, myoblasts as well as muscle tissues of patients with HD 200, 208. Indeed, genetic elimination of PGC‐1α causes enhanced progression of HD, as evaluated by the observing neuronal neurodegeneration and motor coordination 62, 201, which indicates the important contribution of PGC‐1α in HD 201. Moreover, several downstream targets (NRF1, NRF2, and TFAM) of PGC‐1α may be involved in the mitochondrial dysfunction of HD 201. A pathologic grade‐dependent significant decrease in mitochondria numbers in striatal spiny neurons was shown by Kim et al., which was associated with decreases in TFAM and PGC‐1α 204. Moreover, significant decreases in TFAM and PGC‐1α have been reported in both myoblast cultures and muscle biopsies from patients with HD 62, 204. These findings robustly pinpoint decreased expression of PGC‐1α in HD pathogenesis 208.

Interestingly, PGC‐1α promoted removal of protein aggregates and Htt turnover by transcription factor EB (TFEB) activation. TFEB as a main regulator of the autophagy–lysosome pathway is able of decreasing neurotoxicity as well as Htt aggregation, placing PGC‐1α upstream of TFEB and recognizing these two molecules as substantial therapeutic targets in HD and possibly other neurodegenerative disorders resulted from protein misfolding 209 (Figure 6). Quintanilla and his colleagues indicated that activation of PPAR‐γ receptors can ameliorate mitochondrial dysfunction in mHtt‐expressing cells, which has a significant role in the HD pathogenesis 195. PPAR‐γ agonists prevent oxidative stress and attenuate dysfunction of mitochondria in mHtt striatal cells 197 and also challenged with a calcium overload in mHtt‐expressing cells. In addition, PPAR‐γ agonists enhance oxidative capacity of phosphorylation in human and mouse cells and increase mitochondrial biogenesis 210, 211. It was demonstrated that PPAR‐γ agonists could represent a new objective for the advance of therapeutic plans for HD 195. Likewise, AMPK activation induces neuroprotection in HD through promoting mitochondrial biogenesis and elevating cell survival 111. Additionally, overexpression of SIRT1 improves motor function and attenuates mHtt‐mediated metabolic abnormalities by activating PGC‐1α in transgenic mouse models of HD 212. These results propose that the biogenesis pathway of mitochondria can be a potential novel therapeutic target for HD treatment.

Figure 6.

Limitation of the pathological progression, neurodegeneration, and cell death in HD through increasing the PGC‐1α activity as a key regulator of the mitochondrial biogenesis.

ALS

ALS is a progressive adult‐onset neurodegenerative disorder that leads to fatal paralysis. Disease in humans and rodent models initiates with muscle denervation and muscle atrophy following denervation, each arising from degeneration and selective loss of motor neurons in the spinal cord as well as brain 64. Several studies reported that in ALS, mitochondria play as a target for toxicity through decreased mitochondrial Ca²⁺ capacity, altered distribution of axonal mitochondria, abnormal mitochondrial morphology, elevated levels of mitochondrial ROS production, deficits in mitochondrial respiration, and ATP production in the CNS as well as muscles of patients with ALS 64. Morphological and biochemical mitochondrial abnormalities including a reduction in mtDNA copy number and deficiencies in activity of respiratory chain were confirmed in postmortem spinal cords of patients with ALS 65. Specific damage of muscle or neurons can clearly be caused by dysfunction of mitochondria, because mutation/deletion in mitochondrial genes leads to specific muscle and nerve diseases 66. In patients with ALS, mitochondrial dysfunction of skeletal muscle is linked with a decrease in mRNA of the PGC‐1α and PGC‐1β, NRF1, ERRα, Mfn1 and Mfn2, and protein content as well as increases in several miRNAs possibly involved in neuromuscular junction and skeletal muscle regeneration. It suggests that mitochondrial dysfunction in skeletal muscle plays key roles in the pathogenesis of ALS 67. In addition, it was reported that PPAR‐γ might be a main signaling pathway contributing to neuroinflammation, which is considered as one of the hallmarks of ALS 68 (Table 2).

Several previous studies reported changes in mitochondrial ETC. activities in ALS 213. For instance, increased activity of complex I found in postmortem brain tissue may indicate a compensatory incident against the deficit of complex IV enzymes encoded by mtDNA which seen in some patients with ALS. Nevertheless, in postmortem spinal cord tissue from sporadic ALS (sALS) and familial ALS (fALS) cases, a reduction in citrate synthase activity is paralleled by reduction in the activities of complexes I + III, II + III, and IV, which might be seen after a selective loss of mitochondria in spinal cords or increased damage of mtDNA 23 (Figure 2). Moreover, higher levels of oxidized ETC. cofactor Q10 in sALS cerebrospinal fluid and also increased levels of lactate and ROS in their blood have been seen 214. Likewise, oxidative stress has contributed as a part of the pathogenic pathway in ALS and might derive from defective OXPHOS 215.

In addition, ALS has been linked with over 130 different mutations in the Cu/Zn superoxide dismutase (SOD1) gene, yet this toxicity mechanism is still controversial. While it is not completely clear how mitochondria is damaged by mutant SOD1 (mSOD1), some recent research has revealed that ALS‐linked SOD1 mutations are recruited selectively to mitochondria and induce respiratory deficiencies 65. It is also highlighted that accompanying mSOD1‐mediated disease is evidence for alteration of mitochondrial calcium‐loading capacity, impairment of electron transport chain activities particularly in complexes III, increase in aberrant ROS production, and block both protein import at the mitochondrial outer membrane and the antiapoptotic actions of B‐cell lymphoma (2BCL2) 66. Likewise, changes in the activities of respiratory chain complexes were defined in sporadic ALS, exhibiting higher activity of complexes I and II/III in the frontal cortex of SOD1‐related patients with ALS, and reduced activity of complex IV in the spinal cord and individual spinal motor neurons 76. Menzies et al. (2002) reported a particular reduction in activity of complex IV in motor neurons of spinal cord from sporadic cases of ALS 76 (Figure 2).

Denervation‐induced muscle atrophy is considered to be an early event along with changes in mitochondrial morphology and activity within muscle in ALS 64. A significant decrease in mRNA of the PGC‐1α and PGC‐1β, NRF1, ERRα, Mfn1 and Mfn2, protein content as well as subunit IV of the COX mRNA and protein was seen in patients with ALS 67. In patients with ALS, mitochondrial dysfunction of skeletal muscle is related to a decrease in PGC‐1α signaling networks involved in mitochondrial function and biogenesis 67. The PGC‐1α promoted several effects on muscle, such as enhanced mitochondrial activity and mass (Figure 7). Mitochondrial activity and biogenesis are retained via end‐stage disease, together with maintenance of muscle function, delayed muscle atrophy, and considerably improved muscle tolerance even at late stages of disease. Nevertheless, survival was not prolonged; drugs increasing activity of PGC‐1α in muscle show a great treatment for retaining muscle function during ALS progression 64.

Figure 7.

Limitation of the pathological progression, neurodegeneration, and cell death in ALS through increasing the PGC‐1α activity as a key regulator of the mitochondrial biogenesis.

Another possible method to activate the pathway of PGC‐1α, and improving mitochondrial function is through PPARs activation which interact with PGC‐1α and work together with combination of this transcriptional coactivator in the regulation of mitochondrial biogenesis 68. PPAR‐dependent self‐protective mechanisms appear to be relevant for survival of ALS motor neurons 216. PPARs especially PPAR‐γ may be main regulators of neuroinflammation signaling seen in ALS and perhaps a new target for the development of ALS therapeutic strategies. Because neuroinflammatory pathway is one of the hallmarks of ALS, thus, neuroinflammation blockage may have a therapeutic effect on patients with ALS 64, 68. Likewise, inducing mitochondrial biogenesis by AMPK activation may present a promising therapeutic approach in mutant SOD1 mice model of ALS 217. Recently, it was also shown that activation of SIRT1 enhances the survival of motor neurons by activation of PGC‐1α in transgenic mice model of ALS 155. In addition, a recent article identified that SIRT3 protect against mitochondrial fragmentation and neuronal cell death in ALS pathogenesis using a cell‐based model 111. Altogether, these observations strongly suggest that fine‐tuning PPAR‐γ transcriptional activity within the CNS may represent an novel approach to limit the progression of ALS 216.

Conclusion

As highly dynamic organelles, mitochondria have crucial roles in cell survival as well as cell death 1, 2 and able to alter their morphology, number, and function in reaction to stressors and physiological conditions 2. The morphology of mitochondria is controlled by repetitive cycles of mitochondrial fusion and fission machinery which are central to mitochondrial dynamics 18. Altered mitochondrial dynamics as well as mDNA mutations 8, gene mutations 9, impaired transcription contribute to mitochondrial dysfunction 10 which results in the pathogenesis of several diseases 3, 11, 12. Dysfunction and abnormality in mitochondrial dynamics, such as reduced mitochondrial mixing (fusion) and increased mitochondrial fragmentation (fission), are important factors related to the mitochondrial dysfunction, cell death in aging 19, and neurodegenerative diseases, including AD 20, PD 21, HD 22, and ALS 23. Mitochondrial dysfunction is reflected by mtDNA damage and decrease in mitochondrial function, mtRNA transcripts, and protein synthesis 18. Mitochondrial functions are changed in brains of individuals with specific neurodegenerative disorders 70, 71. In addition, dysfunction of ETC. complexes was involved in the pathogenesis of chronic neurodegenerative diseases 72, 73. Regarding these data, mitochondria considered as a potential target for pharmacological‐based therapies 92.

Several lines of evidence demonstrate that mitochondrial biogenesis has a vital role in maintaining mitochondrial homeostasis to meet the physiological requirements of eukaryotic cells 20. Enhanced biogenesis is compatible with the mtDNA copy number and increased mitochondrial gene expression contributed to mitochondrial biogenesis, including PGC‐1α, PGC‐1β, TFAM, NRF1, NRF2, TFB1M, and PPAR‐γ 89. Accordingly, the impaired mitochondrial biogenesis is associated with the mitochondrial dysfunction and has a significant role in the pathogenesis of the neurodegenerative disorders 148. Overall, this data demonstrated induction or improvement of mitochondrial biogenesis alleviates mitochondrial dysfunction and may confirm a modern neuroprotective approach in the near future 91. Altogether, it is strongly suggested that fine‐tuning of transcriptional activities of the mitochondrial biogenesis regulators within the CNS may represent attractive approaches to limit the progression of neurodegenerative diseases.

Conflict of Interest

The authors declare no conflict of interest.