Table 1.

Mitochondrial deficiencies associated with brain degenerative disorders

Disease	Molecular Hallmarks		Cellular Hallmarks	Model		References
Alzheimer's disease (AD)	n.d		Metabolic enzyme dysregulation, favoring the accumulation of tau tangles and Aβ plaques	Non-neural cell types obtained from AD patients		[35–37]
	Increased expression of apoptotic markers		Reduced mitochondrial membrane potential, decreased ATP levels and oxygen consumption	Human neuroblastom a SH-SY5Y non-nucleated cells transplanted with platelet- derived cytoplasm from AD patients		[45]
	Rotenone- induced complex I inhibition		Loss of neurons in the substantia nigra and the striatum, cytoplasmic accumulations of phosphorylated tau. Decrease in ATP levels	Rat		[46, 47]
	Accumulating mitochondrial DNA polymerase mutation		Severe mitochondrial bioenergetic defects	Transgenic mice expressing human AßPP		[48]
	Reduced expression of AßPP and COX1		Forebrain and hippocampal region atrophy. Reduced Aß plaque frequency and reduction of 8OHG+ nuclei	COX deficient mice		[49]
Parkinson's disease (PD)	Complex 1 inhibition		Nigral neuron degeneration	SH-SY5Y cells Rats treated with rotenone		[62, 63]
	Nrf2/Keap1 signaling		Abnormal thermal profile, increased	Mice, rats, and C. elegans		[65, 66]
	Pathway		Oxidative stress, and abnormal dopamine dependent behavior. Mitochondrial related neuronal apoptosis and motor defects	Treated with 6- OHDA
	Severe mt-DNA damage		Elevated levels of co-enzyme Q-10 and 8-OHdG on nigral neurons	Post-mortem samples from PD patients		[71, 72]
	MEF2D binding to mt-DNA sections encoding complex I subunit NADH dehydrogenase		Increased hydrogen peroxide levels, low ATP production and stress-induced cell death	Mice and post mortem PD brains		[75, 76]
	Expression levels of mitochondrial complexes III subunit UQCR2, IV and V subunit ATP5A		Reduced intracellular ATP content	LrrkG2019S knock-in mice and patient- derived fibroblasts		[77]
	Parkin mutation		Reduced mitochondrial complex I activity and intracellular ATP content	Human fibroblasts, drosophila and zebrafish		[79–81]
	Premature stop mutation (Y431*)		Dysfunction of mitochondrial complexes I and III, and loss of dopaminergic neurons	PINK1 mutant zebrafish		[81]
	Down-regulation of various electron carrier proteins		Low complex I- mediated respiration	PINK1 KO rats		[83]
Huntington's disease (HD)	Decrease in CAG repeats		Decrease in ATP content, and respiratory and glycolytic capacities	iPSC-derived from patient fibroblasts		[92]
	Dysregulation of mitochondrial encoded genes associated with electron transport chain subunits		Mitochondrial swallow, loss of cristae organization, suppression of complex III activity and ATP production	Wistar rats exposed to mitochondrial toxins		[93–95]
	Approximately 145 CAG repeats, downregulation of mitochondrial membrane related proteins		Mitochondrial membrane potential and calcium influx are diminished	R6/1 primary striatal neuron		[96]
	Down-regulation of the expression of fusion markers and mitochondrial biogenesis regulators Upregulation of fission markers		Decrease in mitochondrial fragments and ATP generation. Increase in GRPase-DRP1 activity and hydrogen peroxide levels	HdhQ111/Q11 1 neurons		[94, 95]
	Increased oxidative stress markers and reduced expression of mitochondrial biogenesis mediators		Increase in autophagy and ubiquitination of mitochondrial constituents	R6/2 HD mice		[97]
	Mutant Htt interacting with VCP		Mitochondrial fragmentation and increase in mitophagy	Flag-mtVCP- expressing striatal and spiny neurons from R6/2 and YAC128 mice		[98]
	Transgenic expression of human full length Htt (Q97). Htt binding with Drp1		Increase in nitric oxide and S- nitrosylation. Promotion of mitochondrial fragmentation and dendritic spine density	BACHD transgenic rats and postmortem brain samples from HD patients		[89]
Multiple	Disturbed		Calcium	Brain tissue		[122]
Sclerosis (MS)	Oxidative phosphorylation, activation of calcium- dependent proteases		Accumulation, cytoskeletal modifications, and impaired axonal integrity	From patients autopsy
	Dysregulation of the expression of H3K3me3		Change in chromatin dynamics and thus poor transcription of mitochondrial genes	Human SH- SY-5Y neuroblastom a cells		[127]
	Sirtuin deregulation and Rab32- mediated ER stress		Mitochondrial dysfunction and thus progressive neuronal death and MS severity	Primary human fetal neurons		[116]
	n.d		Low respiratory capacity, poor mitochondrial mass and reduced proliferative potential	Peripheral blood cells of MS patients		[114]
	Down-regulation of mitochondrial biomass markers		Ultrastructural mitochondrial abnormalities	Naïve and effector memory CD4+ T cells from MS patients		[114]
Friedreich's ataxia (FA)	Frataxin knock- down, up- regulation of SOD1/2 enzymes		Disturbances in mitochondrial membrane potential and dynamics, elevated protein carbonylation and poor reductive capacity, increased lipid droplet formation	Non-neural cells		[138, 139]
	n.d		Glutathione- dependent mitochondrial oxidative stress and thiol modifications in respiratory chain	Frataxin deficient lymphoblasts		[140, 141]
			complexes III and IV
	Depletion of frataxin expression		Poor neuronal cell area in the dorsal root ganglia	Frataxin- deficient knockin- knockout (Cg- Fxntm1MknFx ntm1Pand/J; KIKO) mice		[144]
	Single GAA repeat sequence in the frataxin gene		Reduced mitochondrial membrane potential, exacerbated ROS generation, defects in the activity of mitochondrial complexes I, II, III and IV, and increased lipid peroxidation and neuronal death	YG8R mice		[146]

n.d.: non-described