Abstract
Mitochondria are involved in a variety of critical cellular functions, and their impairment drives cell injury. The mitochondrial ribosome (mitoribosome) is responsible for the protein synthesis of mitochondrial DNA-encoded genes. These proteins are involved in oxidative phosphorylation, respiration, and ATP production required in the cell. Mitoribosome components originate from both mitochondrial and nuclear genomes. Their dysfunction can be caused by impaired mitochondrial protein synthesis or mitoribosome misassembly, leading to a decline in mitochondrial translation. This decrease can trigger mitochondrial ribosomal stress and contribute to pulmonary cell injury, death, and diseases. This review focuses on the contribution of the impaired mitoribosome structural components and function to respiratory disease pathophysiology. We present recent findings in the fields of lung cancer, chronic obstructive pulmonary disease, interstitial lung disease, and asthma. We also include reports on the mitoribosome dysfunction in pulmonary hypertension, high-altitude pulmonary edema, and bacterial and viral infections. Studies of the mitoribosome alterations in respiratory diseases can lead to novel therapeutic targets.
Keywords: lung, mitochondria, mitoribosome, respiratory diseases
INTRODUCTION
More than 15% of global deaths are associated with chronic obstructive pulmonary disease (COPD), lung cancer, and respiratory infections (1). Thus there is an urgent need to understand the mechanisms of pulmonary dysfunction. Improving our knowledge of impaired lung function can lead to the early detection of disease biomarkers and efficient treatments. Over 40 different cell types are specially organized to compose mammalian lungs (2). These cells contain a different number of mitochondria according to their function and energy demand. Alveolar type II (ATII) cells, which continuously synthesize, release, and recycle surfactant, and bronchial epithelial cells, with cilia beating, are abundant in mitochondria for their high metabolic functions (3, 4). Moreover, a rapidly growing body of scientific literature places mitochondria at the crossroad of lung diseases.
Mitochondria are multifunctional organelles involved in cell metabolism and produce ATP necessary for critical cellular activities (1). They are also an endogenous source of reactive oxygen species (ROS). Around 1–2% of normal cells’ total oxygen consumption rate leads to ROS production (5). ROS can cause cell damage and death (6). Mitochondrial DNA (mtDNA) encodes components that are indispensable for the biogenesis of the oxidative phosphorylation (OXPHOS) complexes (7). Indeed, in humans, it encodes 13 subunits of the respiratory chain complexes (RCC). Electron transport through complexes I to IV is coupled with a proton gradient generation across the inner membrane. In turn, the proton gradient is used by complex V to produce ATP (Table 1). The lung is metabolically active, and its glucose utilization surpasses almost any other organ in the body, including the brain, kidney, and liver (8). The oxygen consumption rate in the lung is almost as great as the liver (9). Lung cells are highly dependent on OXPHOS for their energy needs and are susceptible to mitochondrial dysfunction (10). Moreover, compared with other tissues, mitochondria in the lung possess its specific isoform of electron transport chain (ETC) complex IV, cytochrome c oxidase (COX subunit IV-2). This isoform leads to an advantageous metabolic adaptation to aerobic OXPHOS since it increases by twofold COX oxygen-binding compared with COX in other tissues (11). Indeed, mitochondrial dysfunction, which underlies the pathological mechanisms to predispose, promote, or exacerbate lung diseases, has been demonstrated (10). Interestingly, RCC (except for complex II) and the mitoribosome, which translates the 13 subunits, are the only cellular complexes that possess components encoded in nuclear and mitochondrial genomes. This dual origin needs a tuned and synchronized synthesis since the different subunits’ stoichiometry is crucial for cell homeostasis (12, 13). Mitoribosome stress is the consequence of the deficiency in mitochondrial translation. It can be caused by the impairment of mitoribosome biogenesis leading to its misassembly and dysfunction. The assembly of mitoribosome is a complex series of events in which numerous factors are involved. Several diseases are linked to different pathogenic mutations of mitoribosomal proteins that impair mitoribosome biogenesis and translation activity (14). Mitoribosomes are essential for the efficient translation of fully functional OXPHOS systems. Therefore, affecting the precise function of the OXPHOS components by alterations in the mitochondrial translation machinery will decrease the abundance or efficiency of RCC and disrupt the OXPHOS process.
Table 1.
Human mitochondrial DNA genes, proteins, and their function
| Gene | Derived Products |
Function | |
|---|---|---|---|
| RNA | Protein/Peptide | ||
| MT-ATP6 | mRNA ATP6 | ATP synthase, F0 subunit 6 | Respiratory chain complex V |
| MT-ATP8 | mRNA ATP8 | ATP synthase, F0 subunit 8 | Respiratory chain complex V |
| MT-CO1 | mRNA CO1 | Cytochrome c oxidase, subunit 1 | Respiratory chain complex IV |
| MT-CO2 | mRNA CO2 | Cytochrome c oxidase, subunit 2 | Respiratory chain complex IV |
| MT-CO3 | mRNA CO3 | Cytochrome c oxidase, subunit 3 | Respiratory chain complex IV |
| MT-CYB | mRNA CYB | Cytochrome b | Respiratory chain complex III |
| MT-ND1 | mRNA ND1 | NADH dehydrogenase, subunit 1 | Respiratory chain complex I |
| MT-ND2 | mRNA ND2 | NADH dehydrogenase, subunit 2 | Respiratory chain complex I |
| MT-ND3 | mRNA ND3 | NADH dehydrogenase, subunit 3 | Respiratory chain complex I |
| MT-ND4 | mRNA ND4 | NADH dehydrogenase, subunit 4 | Respiratory chain complex I |
| MT-ND4L | mRNA ND4L | NADH dehydrogenase, subunit 4L | Respiratory chain complex I |
| MT-ND5 | mRNA ND5 | NADH dehydrogenase, subunit 5 | Respiratory chain complex I |
| MT-ND6 | mRNA ND6 | NADH dehydrogenase, subunit 6 | Respiratory chain complex I |
| MT-RNR1 | 12S rRNA | MOTS-c | mt-ribosome, metabolism |
| MT-RNR2 | 16S rRNA | Humanin (21 aa), SHLP1-6 | mt-ribosome, cytoprotection, metabolism, signaling, senescence |
| ASncmtRNA1 and 2 | – | mt-ribosome, cytoprotection, metabolism, signaling, senescence | |
| SncmtRNA | – | mt-ribosome, cytoprotection, metabolism, signaling, senescence | |
| MT-TV | tRNAVal | – | mRNA decoding, mt-ribosome |
| MT-TA | tRNAAla | – | mRNA decoding |
| MT-TC | tRNACys | – | mRNA decoding |
| MT-TD | tRNAAsp | – | mRNA decoding |
| MT-TE | tRNAGlu | – | mRNA decoding |
| MT-TF | tRNAPhe | – | mRNA decoding |
| MT-TG | tRNAGly | – | mRNA decoding |
| MT-TH | tRNAHis | – | mRNA decoding |
| MT-TI | tRNAIle | – | mRNA decoding |
| MT-TK | tRNALys | – | mRNA decoding |
| MT-TL1 | tRNALeu (UUR) | – | mRNA decoding |
| MT-TL2 | tRNALeu (CUN) | – | mRNA decoding |
| MT-TM | tRNAMet | – | mRNA decoding |
| MT-TN | tRNAAsn | – | mRNA decoding |
| MT-TP | tRNAPro | – | mRNA decoding |
| MT-TQ | tRNAGln | – | mRNA decoding |
| MT-TR | tRNAArg | – | mRNA decoding |
| MT-TS1 | tRNASer (UCN) | – | mRNA decoding |
| MT-TS2 | tRNASer (AGY) | – | mRNA decoding |
| MT-TT | tRNAThr | – | mRNA decoding |
| MT-TW | tRNATrp | – | mRNA decoding |
| MT-TY | tRNATyr | – | mRNA decoding |
–, not applicable.
Thus mitochondrial translational machinery defects may dramatically interfere with mitochondrial function and can contribute to pulmonary disease. Here, we conducted a comprehensive review of recent findings regarding ribosomal RNA (rRNA) and proteins that constitute the mitoribosome, their genetic regulation, and their association with respiratory dysfunction.
MITORIBOSOME
Biogenesis
The human mtDNA is transcribed into two polycistronic RNAs that are processed into 2 rRNAs, 22 transfer RNAs (tRNA), and 13 messenger RNAs (mRNAs) (Table 1) (15). Mitochondrial protein synthesis, which is different from its cytosolic counterpart, carries hallmarks of its alphaproteobacterial origin and new and unique features that have evolved. Indeed, mitochondrial translation machinery uses 22 noncanonical tRNAs instead of 45 and 46 in the bacterial and cytosolic translation systems, respectively. It also has a different genetic code than the universal one, in addition to distinct codon usage; e.g., the standard stop codon UGA is a codon for tryptophan in mitochondria.
The mitoribosome is a ribonucleoprotein complex composed of an rRNA core and peripheral ribosomal proteins (16). Mitochondrial rRNAs are reduced in number and size compared with the bacterial ones and partially compensated with proteins. Consequently, this results in a reversed protein to the RNA mass ratio of 2:1, unlike the ratio of 1:2 in the bacterial ribosome. Mitoribosome has a sedimentation coefficient of 55S and is composed of large 39S and small 28S subunits (Table 2). On the other hand, the small mitochondrial subunit (mtSSU) is composed of 12S rRNA encoded by MT-RNR1 and 30 mitochondrial ribosomal proteins (MRPs) (Table 3). Bacterial 5S rRNA is absent in the mammalian mitoribosome and is replaced by tRNAVal in humans (15). Incorporating this specific tRNA is likely due to its location between 12S and 16S rRNAs in the polycistronic transcript. Of note, a new nomenclature based on the conservation of MRPs has been recently proposed to distinguish between universal (u) and conserved among living organisms of bacterial origin (b) and specific to mitochondria (m) (50).
Table 2.
Human mitochondrial large subunit components and their contribution to lung diseases
| Component | Disease | Cell Types and Animal Models |
|---|---|---|
| 16S rRNA | Asthma | Blood (17) |
| COPD | Muscle tissue (18, 19) LHCN-M2 cell line, mice (18) |
|
| HAPE | Patients mt DNA (sample not specified) (20) |
|
| Infection | PBMC (21) | |
| Inhibition | RLE cells (22) Blood (23) |
|
| Lung cancer | H292 cell line (24) | |
| tRNAVal | ND | |
| uL1m (MRPL1) | Lung cancer | Lung tissue (25) H460 cell line (26) |
| uL2m (MRPL2) | Lung cancer | Lung cancer (27) |
| uL3m (MRPL3) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| uL4m (MRPL4) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| bL9m (MRPL9) | PH | Murine lung (21) |
| uL10m (MRPL10) | COPD | Lung tissue (29) |
| Lung cancer | Lung tissue (30)DLD1 and HTC116 cell lines (28) | |
| PH | Murine lung (21) | |
| uL11m (MRPL11) | Lung cancer | Lung tissue (27, 30) DLD1 and HTC116 cell lines (28) |
| bL12m (MRPL7/L12) | COPD | Lung tissue (31, 32) |
| Inhibition | HFL-1 cell line (33) | |
| Lung cancer | Lung tissue (27)DLD1 and HTC116 cell lines (28) | |
| uL13m (MRPL13) | Lung cancer | Lung tissue (27) |
| PH | Murine lung (24) | |
| uL14m (MRPL14) | Asthma | Data mining (34) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| uL15m (MRPL15) | Lung cancer | Lung tissue (27, 30) |
| uL16m (MRPL16) | Lung cancer | Lung tissue (27, 30) |
| bL17m (MRPL17) | Lung cancer | Lung tissue (27) |
| PH | Murine lung (21) | |
| uL18m (MRPL18) | ND | |
| bL19m (MRPL19) | Lung cancer | Lung tissue (30) |
| PH | Murine lung (21) | |
| bL20m (MRPL20) | COPD | Lung tissue (27) |
| Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
|
| PH | Murine lung (21) | |
| bL21m (MRPL21) | COPD | Lung tissue (35) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| uL22m (MRPL22) | ND | |
| uL23m (MRPL23) | COPD | Lung tissue (32) |
| Lung cancer | Lung tissue (27, 36) | |
| PH | Murine lung (21) | |
| uL24m (MRPL24) | COPD | Lung tissue (29) |
| Lung cancer | Lung tissue (27) | |
| PH | Murine lung (21) | |
| bL27m (MRPL27) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| PH | Mice lung (21) | |
| bL28m (MRPL28) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| PH | Murine lung (21) | |
| uL29m (MRPL47) | Infection | BHK-21 and SCR-1 cell lines (37) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| uL30m (MRPL30) | ND | |
| bL31m (MRPL55) | ND | |
| bL32m (MRPL32) | COPD | Lung tissue (29) |
| bL33m (MRPL33) | Lung cancer | Lung tissue (27, 30) |
| bL34m (MRPL34) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| PH | Murine lung (21) | |
| bL35m (MRPL35) | Lung cancer | Lung tissue (27) |
| PH | Murine lung (21) | |
| bL36m (MRPL36) | Asthma | Data mining (34) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| mL37 (MRPL37) | COPD | Lung tissue (29) |
| mL38 (MRPL38) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| PH | Mice lung (21) | |
| mL39 (MRPL39) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| mL40 (MRPL40) | COPD | Lung tissue (29) |
| Lung cancer | Lung tissue (27) | |
| PH | Murine lung (21) | |
| mL41 (MRPL41) | Lung cancer | Lung tissue, mice, SCLC (e.g., H211 cell line), and NSCLC (e.g., H1299 cell line) (38) DLD1 and HTC116 cell lines (28) |
| PH | Murine lung (21) | |
| mL42 (MRPL42) | Asthma | Circulating T cells (39) |
| Lung cancer | Lung tissue (27) | |
| PH | Murine lung (21) | |
| mL43 (MRPL43) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| Sarcoidosis | Bronchoalveolar lavage (40) | |
| mL44 (MRPL44) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| mL45 (MRPL45) | COPD | Lung tissue (29, 31) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| PH | Murine lung (21) | |
| mL46 (MRPL46) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| mL48 (MRPL48) | Lung cancer | Lung tissue (27) |
| PH | Murine lung (21) | |
| mL49 (MRPL49) | Lung cancer | Lung tissue (27) |
| mL50 (MRPL50) | ND | |
| mL51 (MRPL51) | COPD | Lung tissue (29) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| mL52 (MRPL52) | Asthma | Data mining (34) |
| Lung cancer | Lung tissue (27) CT26 cell line (28) |
|
| mL53 (MRPL53) | ND | |
| mL54 (MRPL54) | PH | Murine lung (21) |
| mL62 (MRPL58, ICT1) | ND | |
| mL63 (MRP63) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| mL64 (MRPL59, CRIF1) | ND | |
| mL65 (MRPS30) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| mL66 (MRPS18A) | Lung cancer | DLD1 and HTC116 cell lines (28) |
L, large; S, small; u, universal; b, bacterial; m, mitochondrial; MRP, mitochondrial ribosomal protein; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; HAPE, high-altitude pulmonary edema; PH, pulmonary hypertension; MRP, RLE, rat lung epithelial cell; PBMC, peripheral blood mononuclear cell; NSCLC, nonsmall cell lung cancer; SCLC, small cell lung cancer; ND, not determined. References are shown in parenthesis.
Table 3.
Human mitochondrial small subunit components and their contribution to lung diseases
| Component | Disease | Cell Types and Animal Models |
|---|---|---|
| 12S rRNA | COPD | Muscle tissue (18, 19, 41) LHCN-M2 cell line, murine muscle (18) |
| HAPE | Patient’s samples (20) | |
| Infection | PBMC (42) | |
| Inhibition | Blood (43) W1-38 cell line (44) |
|
| IPF | Alveolar macrophage (45) | |
| Lung cancer | Lung tissue (46) | |
| uS2m (MRPS2) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| PH | Mice lung (21) | |
| uS3m (MRPS24) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| uS5m (MRPS5) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| bS6m (MRPS6) | Infection | Macaque lung (47) |
| uS7m (MRPS7) | Lung cancer | Lung tissue (27) |
| uS9m (MRPS9) | ND | |
| uS10m (MRPS10) | COPD | LHCN-M2 cell line (18) |
| uS11m (MRPS11) | Lung cancer | Lung tissue (27, 30) DLD1 and HTC116 cell lines (28) |
| uS12m (MRPS12) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| PH | Murine lung (21) | |
| uS14m (MRPS14) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| uS15m (MRPS15) | Lung cancer | Lung tissue (27) |
| bS16m (MRPS16) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| uS17m (MRPS17) | Asthma | Data mining (34) |
| mS40 (MRPS18B) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| bS18m (MRPS18C) | ND | |
| bS21m (MRPS21) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| PH | Murine lung (21) | |
| mS22 (MRPS22) | COPD | Lung tissue (48) |
| Lung cancer | DLD1 and HTC116 cell lines (28) | |
| mS23 (MRPS23) | ND | |
| mS25 (MRPS25) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| mS26 (MRPS26) | Lung cancer | DLD1 and HTC116 cell lines (28) |
| mS27 (MRPS27) | Lung cancer | Lung tissue (27) |
| bS1m (MRPS28) | Lung cancer | Lung tissue (27) A549 and H1299 cell lines (49) |
| mS29 (MRPS29) | ND | |
| mS31 (MRPS31) | Lung cancer | Lung tissue (27) |
| mS33 (MRPS33) | Lung cancer | Lung tissue (27) |
| mS34 (MRPS34) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| mS35 (MRPS35) | Lung cancer | Lung tissue (27) DLD1 and HTC116 cell lines (28) |
| mS37 (MRPS37) | ND | |
| mS38 (MRPS38) | ND | |
| mS39 (MRPS39, PTCD3) | ND |
S, small; u, universal; b, bacterial; m, mitochondrial; MRP, mitochondrial ribosomal protein; IPF, idiopathic pulmonary fibrosis; COPD, chronic obstructive pulmonary disease; HAPE, high-altitude pulmonary edema; PH, pulmonary hypertension; PBMC, peripheral blood mononuclear cell; ND, not determined. References are shown in parenthesis.
About 1,500 proteins are translated in the cytosol and imported into mitochondria to fulfill the different mitochondrial functions depending on the cell type. In addition to MRPs, several imported proteins are involved in the assembly and required for mitoribosome formation, including RNA modifying enzymes (e.g., MRM1), GTPases (e.g., ERAL1), and RNA helicases (e.g., DDX28). These cofactors are as crucial as MRPs and their mutations are often associated with severe diseases (16). In contrast, all RNA components required for mitochondrial translation are provided by mtDNA.
Moreover, a recent study showed that treatment with tetracycline antibiotics, which inhibit mitochondrial protein synthesis, leads to decreased lung tissue damage and an increased repair in a mouse model of bacterial sepsis. However, different effects were observed in the liver (51). Therefore, the role of mitoribosome in tissue injury and repair in various cell types requires further thorough examination.
Structure and Function
The mitoribosome is essential for synthesizing the major subunits of all ETC of the OXPHOS machinery (52). Mitoribosome translates uncapped mRNAs of 13 subunits of the RCC. Several short open reading frames have been detected in 12S and 16S rRNAs translated into short peptides in humans (Table 1). The mitochondrial translation system has retained some prokaryotic functional characteristics, such as initiating protein synthesis with N-formylmethionine (15). Moreover, the mitoribosome’s catalytic core is conserved where mitochondrial large subunit (mtLSU) catalyzes the peptidyl-transferase reaction, and mtSSU is used as a platform for mRNA binding and decoding. This conservation can be perceived through the inhibition of mitoribosome with some antibiotic families inhibiting bacterial ribosomes. However, considerable differences exist at the structural level despite the functional similarities.
The human mitoribosome’s high-resolution structure obtained by cryogenic electron microscopy has uncovered important molecular details regarding protein localization, interaction, and arrangement (53). This analysis has dramatically improved our understanding of the evolutionary divergences of ribosomes of other species. It also explained the human mitoribosome’s flexibility to accommodate noncanonical tRNAs and leaderless mRNAs. For instance, it has been shown that the mRNA channel entrance is wide and formed by uS3m and uS5m in the mitoribosome, while in bacteria, it is formed by uS3, uS5, and uS4. Moreover, uS4 is absent in mitochondria.
Interestingly, MRPs have other roles in addition to compensating truncated rRNA (54). For example, mL45 allows the anchorage of the mitoribosome to the inner membrane and facilitates the nascent polypeptides’ insertion into their target membrane. Moreover, besides MRPs’ involvement in mitoribosome formation, some other proteins have alternative functions in different cellular processes and pathways, such as apoptosis (mL65, mL41, and mS29) and mitochondrial transcription (mL12) (55).
MITORIBOSOME DYSFUNCTION IN LUNG DISEASES
The Impairment of Mitoribosome Large Subunit
Mitoribosome protein instability and mutations can cause mitochondrial dysfunction, leading to several disorders (16). Mitochondria play a crucial role in the induction of apoptosis, which is essential in tumor treatment. Lung cancer is one of the most common cancers worldwide (30). mtLSU is composed of 16S rRNA, 52 MRPLs, and structural tRNAVal. Carcinogenesis involves a series of changes in mitochondrial genes. A comparison between control and lung cancer tissue has revealed the alteration of numerous mitoribosome genes composing mtLSU. Indeed, uL11m, bL19m, and bL33m were downregulated while uL10m and uL16m were upregulated in tumors. Another study also demonstrated the high expression of 21 MRPLs (e.g., uL23m and mL48) in lung cancer (Table 2) (27). Moreover, it has been shown that uL23m is predominantly expressed in lung cancer metastasis (36). Nonsmall cell lung cancer (NSCLC) represents >80% of lung cancers, and ∼15% is small cell lung cancer. K-RAS mutations are present in 16% to 40% of NSCLC patients. Using whole-genome CRISPR loss-of-function and shRNA screenings, Martin et al. (28) have discovered several synthetic lethal genes combined with K-RAS mutations, including mitoribosome proteins, e.g., bL28m, and mL41. It was shown that mL41, in association with p53 and p27Kip1, is directly linked to cell growth suppression and apoptosis (38). Its expression has been downregulated in tumor tissues, and its ectopic expression in cell lines and mice inhibited cell and tumor growth, respectively. Curcumin and its derived molecules exhibit anti-inflammatory, anti-oxidative, and anti-tumor properties (26). Treatment of H460 lung cancer cell line with demethoxycurcumin has resulted in differential expression of several genes involved in the cell cycle, DNA damage, and apoptosis pathways, among which uL1m has been significantly upregulated. Moreover, another study has reported a new mutation in uL1m (Tyr87Cys) in human asbestos-associated lung cancer (25). Although the exact mechanism remains unknown, these studies showed an increasing evidence of the involvement of MRPLs in this disease.
mtLSU dysfunction was also reported in COPD, characterized by chronic inflammation, which leads to structural disruption and functional limitation of the lung affecting multiple cell types. Mitochondrial dysfunction plays an undeniably crucial role in this disease’s pathogenesis. The difference in gene expressions in control and COPD lung tissue was determined by RNA sequencing. Mitochondrial ribosomal proteins such as bL21m were significantly reduced in COPD (35). Also, mL45 gene expression was lower in patients with this disease without emphysema (31). Furthermore, decreased bL12m and uL23m levels were observed in individuals with emphysema with alpha-1-antitrypsin (AAT) deficiency (32). Using a computational protein localization prediction, Ham et al. (29) detected changes in subcellular localization of mitochondrial proteins, including mitochondrial ribosomal proteins, e.g., mL37 in COPD (Table 2). They also suggested that their mislocalization can contribute to this disease’s pathophysiology.
Sarcoidosis belongs to interstitial lung disease (ILD) and is a systemic inflammatory disease mainly affecting the lung and lymph nodes (56). Studies showed the involvement of the mtLSU in its development. Although sarcoidosis etiology is not well known, clinical reports indicate the impairment of mitochondrial function. Indeed, high autoantibodies levels reactive to four different proteins were detected in bronchoalveolar lavage (BAL) fluid and serum obtained from patients with this disease by antigen microarrays (40). In addition to ZNF688, NCOA2, and ARFGAP1, reactivity has been detected against the mL43 protein of the mtLSU. This study has shown a link between sarcoidosis and mitoribosome, although it has not explored the role of mL43 in this disease pathophysiology. An excessive extracellular mtDNA has been detected in both BAL fluid and plasma in sarcoidosis. Alveolar macrophages exhibited an altered proteome with oxidative phosphorylation and pyruvate metabolism pathways downregulated and upregulated, respectively, in patients with this disease (64). Interestingly, it was reported that a deficiency in complex II of the respiratory chain caused myopathy along with sarcoidosis (65).
Asthma is a chronic disease resulting from complex interactions of environmental factors and genetic susceptibility, characterized by an inflammatory response (57). Mutations or single nucleotide polymorphisms (SNPs) were detected in uL14m, bL36m, and mL52 mitoribosome proteins in this disease (34). Moreover, it has been suggested that PDHA1 and mL42 in CD8+ T cells might be used as specific biomarkers of severe asthma development (39). Notably, a recent study identified MRPL44 association with various asthma and allergy-related traits (58).
Pulmonary hypertension (PH) mainly affects endothelial cells and alters the pulmonary artery’s pressure (21). A study of hypoxia-induced PH in rats has revealed alterations of several mitochondrial genes in the lung. Along with OXPHOS genes, the expression of some mitochondrial ribosomal genes from both subunits has been altered in the PH rat model. It was reported that uL10m and bL17m were upregulated while mL48 were downregulated in lung tissue in PH.
At the time of writing this review, there are 448,146,715 cases, and over 6,009,338 people have died worldwide of the coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. There are 187,469 publications related to this disease; however, none of them includes studies of mitoribosome function to our knowledge. Only three studies on Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV reported alterations in mitoribosome components’ expression (37, 42, 47). Falzarano et al. (47) infected rhesus macaques with MERS-CoV followed by treatment with INF-α2b and ribavirin. This treatment decreased the expression of several lung genes, including bS6m, leading to reduced viral infection and improved outcomes. The BHK-21 cell line expressing SARS-CoV replicon (SCR-1) was engineered to identify host proteins essential for SARS-CoV RNA replication. These cells displayed altered levels of 74 proteins, among which uL29m were downregulated compared with parental cells (37), suggesting that SARS-CoV replication in host cells inhibits the mitochondrial translational machinery.
To summarize, mutations and impairment of the steady-state protein levels in mitoribosome components can contribute to lung diseases. However, it remains to be evaluated whether alterations in MRPs functions are critical in pulmonary abnormalities.
Dysregulation of Mitoribosome 16S rRNA
In addition to MRPLs, mtLSU is also composed of 16S rRNA and the structural tRNA valine. Genetic association studies in asthma have highlighted different mutations or SNPs in mitochondrial- and nuclear-encoded mitochondrial genes, such as tRNAs and 16S rRNA (17). Moreover, a comparison of bronchial epithelial cells obtained from healthy and mild asthmatic patients has revealed a significant downregulation of mitochondrial-encoded gene expression, including 16S rRNA, in this disease (59). Further studies are needed to determine the role of rRNA in mitochondrial translation machinery dysfunction in the pathogenesis of lung diseases.
Changes in altitude levels can decrease lung function due to differential atmospheric pressure and oxygen availability (20). These hypoxic conditions can cause high-altitude pulmonary edema (HAPE). A study conducted on the Han Chinese population compared mitochondrial haplogroups with susceptibility to HAPE. Obtained results have shown that haplogroup D4 confers resistance and haplogroup B contribute to this disease’s genetic risk. Therefore, it has been proposed that 3010 A mtSNP located in the MT-RNR2 gene of haplogroup D4 can enhance the stability of 16S rRNA and protect against HAPE by reducing oxidative stress.
Analysis of peripheral blood mononuclear cells (PBMCs) obtained from convalescent SARS-CoV infected patients has demonstrated alterations of mitochondrial-encoded genes such as upregulation of 16S rRNAs (42). Long noncoding RNAs (lncRNAs) emerge as important players in the regulation of gene expression. They are involved in both normal organ growth and tumorigenesis in the lung. It has been discovered that MT-RNR2 transcripts can form chimeric-long noncoding molecules (SncmtRNA and ASncmtRNAs) that are differentially expressed in healthy and cancerous cells (24). It has also been shown that downregulation of ASncmtRNA, using antisense oligonucleotides, increased susceptibility of different cancer cell lines, including H292 cells, to apoptosis. Escaping apoptosis is an essential feature in tumorigenesis, supporting the mitoribosome’s important role in this process. There is accumulating evidence that mitochondrial dysfunction plays a key role in the pathogenesis of lung cancer. However, the contribution of mitoribosomes alterations to mitochondrial abnormalities in tumor development remains to be determined.
Structural tRNA Valine Dysfunction
Mutations in mt-tRNAs are strongly associated with mitochondrial diseases (60). Indeed, it has been reported that more than 300 mutations in mt-tRNA genes are pathogenic (61). Recent cryoelectron microscopy studies have shown the structural role of mitochondrial tRNAVal in mtLSU (53), which interacts with mL46, mL40, mL48, uL18m, mL38, and bL27m. It was reported that 200 blood samples obtained from NSCLC patients exhibited four mutations/SNPs in mt-tRNAs alanine, leucine (CUN), serine (UCN), and threonine, which have been considered as pathogenic and associated with lung cancer (62). Also, SNPs in mt-tRNAs (arginine, glutamine, threonine, and UCN isoacceptor of serine) and other mitochondrial genes were correlated with fibrosis (63). In addition, several mtSNPs have been associated with sarcoidosis pathophysiology, including mtSNPs in mt-tRNAs within arginine, glutamine, threonine, histidine, tryptophan, tyrosine, cysteine, glycine, and serine (UCN codon isoacceptor) (63). Mutations in the MT-TV gene have been correlated with several diseases. However, there are no reports that explore mt-tRNA valine sequences in lung diseases. mtLSU disorders may lead to mitochondrial dysfunction with respiratory defects and cause severe clinical symptoms. Deep mechanistic studies associating impairment of mtLSU, mitochondrial translation defect, and lung disease development and progression are still needed.
The Impairment of Mitoribosome Small Subunit
mtSSU is composed of 12S rRNA and 30 encoded mitochondrial ribosomal proteins. It has also been demonstrated the involvement of mtSSU in lung diseases. High expression of 15 MRPSs (e.g., uS7m and uS12m) was associated with poor clinical outcome and overall survival in lung cancer patients (Table 2) (27). Also, synthetic lethal genes combined with K-RAS mutations in NSCLC patients screen identified mitoribosome proteins composing mtSSU, e.g., uS3m (Table 2) (28). Radioresistance is a major clinical issue undermining radiotherapy treatment efficiency in these patients and leads to cancer recurrence and metastasis (49). It has been shown that ionizing radiation induced SRSF1 expression in A549 and H1299 cell lines, which caused alternative splicing of several genes, including bS1m. These alternative splicing events were associated with the radioresistance of cancer cells.
In addition to lung cancer, mtSSU is also involved in other respiratory diseases. Mutations or SNPs were also detected in uS17m mitoribosome proteins in asthma (34). However, there are very limited reports regarding mitoribosome function in this disease, and further studies are needed.
Moreover, it was reported that uS2m was downregulated in lung tissue in the PH rat model (21). However, further studies in human lungs are needed to link the mitoribosome with this disease.
Furthermore, proteins uS7m, uS12m, uS17m, and bS1m are among the early MRPs binding proteins to start the assembly of mtSSU. These proteins are mostly involved in forming the outer surface of the mt-SSU, while late-binding proteins, including uS3m and uS10m MRPs, are engaged in preventing premature mitoribosome assembly (68). Therefore, depletion of mtSSU may influence mitoribosome assembly and function, leading to a failure to assemble RCC, mitochondrial dysfunction, and lung diseases.
Mitoribosome 12S rRNA Deficiency
Decreased activities of multiple OXPHOS enzymes due to mutations in mtDNA-encoded 12S rRNA cause a mitochondrial disorder associated with lung diseases. Kazdal et al. (46) have monitored the prevalence of somatic mitochondrial mutations in 352 patients with NSCLC. Although they have shown that ATP6, D-Loop, and 12S rRNA genes displayed the highest mutation to basepair ratio, their results did not reveal evident lung cancer-specific mutations. Several genetic determinants can explain it, such as heteroplasmy level and the threshold effect regulating clinical manifestations (69). Heteroplasmy is a condition where mutated mtDNA coexists with normal mtDNA. Furthermore, different types of tissues have various bioenergetic thresholds. Therefore, the heteroplasmy levels causing mitochondrial dysfunction greater than the bioenergetic threshold will manifest biochemical defects (70). Moreover, mutated mtDNA leads to clinical disorders in a tissue-dependent manner.
Studies were also performed using quadriceps muscle biopsies obtained from COPD patients (41). The respiratory chain complex IV activity was increased in these patients with chronic respiratory failure compared with controls. Also, 12S rRNA expression was higher while COX1 mRNA was unchanged. Other reports focused on miRNAs expression in muscle biopsies in this disease (18, 19). Overexpression of miR-542-3p and miR-542-5p led to the reduction of the 12S-to-16S rRNAs ratio. Interestingly, miR-542-3p and miR-542-5p have been predicted to target some mitoribosome proteins. It has been shown that transfection of LHCN-M2 cells with miR-352-3p inhibited mitochondrial function, decreased 12S and 16S rRNA expression, and downregulated uS10m (18). Similar results have been obtained in mice. From the above studies, it is clear that mitoribosome can play an essential role in COPD. However, to our knowledge, studies of the direct link and the implication of mitoribosome proteins in this disease pathogenesis are still missing. Idiopathic pulmonary fibrosis (IPF) belongs to ILD and is a chronic lung disease characterized by progressive pathological fibrotic scarring, with several hallmarks of accelerated senescence (66). An aging-associated mitochondrial dysfunction has been identified in pulmonary cells in IPF patients, e.g., reduced mitochondrial respiration and oxygen consumption, which led to decreased ATP generation and increased mtROS production.
Different mitochondrial parameters have also been studied in alveolar macrophages isolated from IPF patients. It was reported that mitochondria displayed morphological alterations, high mtROS, and impaired transcription of OXPHOS genes in IPF (45). A decreased expression of 12S rRNA was also detected in this disease, which is the main component of mtSSU, together with reduced ND1 and ATP6 mRNAs expression. Increased mtDNA release to the cytosol induced senescence of pulmonary fibroblasts through the activation of cyclic GMP-AMP synthase (cGAS)/STING pathway (66). Transgenic mice overexpressing mtDNA base excision repair enzyme mtOGG1 were protected against induced pulmonary fibrosis (67). They also displayed decreased apoptosis and mtDNA damage in alveolar epithelial cells. While mitochondrial disorders and multiple OXPHOS enzyme deficiencies play a role in IPF, further studies are needed to determine the molecular mechanisms of mitochondrial translation machinery dysfunction in the pathogenesis of this disease.
A recent study showed an upregulation of 12S rRNAs obtained from PBMCs from convalescent SARS-CoV-infected patients (42).
To our knowledge, there is no report on mitoribosome function in acute lung injury, acute respiratory distress syndrome, or combined pulmonary fibrosis and emphysema. Therefore, further studies are needed to improve our knowledge of these diseases’ pathogenesis and identify novel therapeutic targets.
There are many complex simultaneous interplays between maintaining mitoribosome function and mitochondria efficiency in ATP production in the lung. Considering that many factors are involved in mitochondrial translation machinery, its defect can result in an OXPHOS complex deficiency linked to respiratory diseases. These diseases may be characterized by a bioenergetic imbalance between mitochondria’s energy production and lung performance demands.
Mitoribosome Response
It has been reported that exposure of rat lung epithelial cells to nitric oxide, asbestos, or H2O2 altered 16S rRNA and NADH dehydrogenase expression (22). D’Anna et al. (33) have detected seven upregulated proteins, including bL12m, after treating normal lung HFL-1 fibroblasts with cigarette smoke extract using two-dimensional electrophoresis and mass spectrometry. Interestingly, bL12m has been shown to interact with mitochondrial RNA polymerase POLRMT, which connects mitochondrial transcription and translation (55). Moreover, treating normal human lung W1-38 fibroblasts with cisplatin increased lipid peroxidation and 12S rRNA levels (44).
Aminoglycosides are used to treat bacterial infections by binding to the bacterial small ribosomal subunit (43, 71). These antibiotics can also bind to the mitoribosome, which has a bacterial origin, leading to nephrotoxicity and ototoxicity in humans. The effect of genetic variations that can aggravate the observed symptoms has been explored. It has been shown that the severity of hearing loss was associated with A1555G mtSNP located in the 12S rRNA encoded by MT-RNR1 gene.
Linezolid belongs to oxazolidinones, and it is used to treat, among others, Streptococcus pneumoniae and Staphylococcus aureus infections (23). This antibiotic blocks bacterial protein synthesis and can cause mitotoxicity through its interaction with 16S rRNA. A2706G polymorphism of the 16S rRNA increased the risk of linezolid-induced toxicity; however, it is still controversial since there are high levels of this mtSNP in the population.
To summarize, mitoribosome relies on numerous factors which coordinate its assembly and assure appropriate mitochondrial translation efficiency (15, 72). Therefore, defects in mitochondrial translation can play critical roles in the pathophysiology of lung diseases (Fig. 1). This includes but is not limited to alteration of mitoribosomes biogenesis and the assembly which can impair mitochondrial translation efficiency and fidelity (73, 74). Furthermore, these mitoribosome abnormalities are associated with OXPHOS machinery dysfunction. However, the specific alterations of the mitoribosome, linked to particular lung disease, are still not well known. Therefore, further research is necessary to understand mitochondrial translation to develop effective therapies for mitoribosome defects.
Figure 1.
Lung diseases affect the mitoribosome structure. IPF, idiopathic pulmonary fibrosis; HAPE, high-altitude pulmonary edema; COPD, chronic obstructive pulmonary disease; MRPs, mitochondrial ribosomal proteins; PH, pulmonary hypertension; mtRNA, mitochondrial RNA; rRNA, ribosomal RNA; OXPHOS, oxidative phosphorylation.
CONCLUSIONS
Although research on lung disease pathophysiology has been extensive in the last decades, early diagnosis and effective treatments are still needed. Advances in structural biology are substantially increasing our knowledge of the mitoribosome function. Recent studies discussed in this review suggest that alterations in rRNAs and MRPs can destabilize the mitoribosome subunits assembly and induce mitochondrial ribosomal stress. This can lead to the deficiency of mitochondrial RCC activity and contribute to lung diseases. Thus defects in mitochondrial translation can contribute to pulmonary abnormalities. It is critical to improve our knowledge of the mitochondrial translation machinery and determine further the role of mitoribosome biogenesis and assembly in the lung.
We have little understanding of the alterations generated during the mitoribosome subunit assembly. Presumably, errors can be resolved quickly by surveillance mechanisms without inducing mitoribosome stress. However, a high load of the dysfunctional structural mitoribosome subunits and a failure in their quality control can lead to pulmonary abnormalities. Also, it is unclear whether mitoribosomal stress is constantly present and whether pathophysiology can result from the inadequate homeostatic response. Moreover, little is known about the molecular mechanisms underlying mitoribosome subunit assembly or mitoribosome components biogenesis in respiratory abnormalities. Testing these avenues can be exciting for future research. These studies can identify new innovative options targeting mitoribosome for early diagnosis and therapeutic strategies in lung diseases.
GRANTS
This work was supported by National Institutes of Health (NIH) Grants R01 ES032081 and R01 HL150587 and Department of Defense Grant W81XWH2110414 (to B.K.) and NIH Grant R21 ES030808, a Catalyst Award from the American Lung Association, and Department of Defense Grant W81XWH2110400 (to K.B.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
L.K. and K.B. drafted manuscript; L.K., B.K., and K.B. edited and revised manuscript; L.K., B.K., and K.B. approved final version of manuscript.
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