bims-mitpro Biomed News
on Mitochondrial Proteostasis
Issue of 2023–10–15
fiveteen papers selected by
Andreas Kohler, Umeå University
  1. Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
  2. Dual roles of UPRer and UPRmt in neurodegenerative diseases.
  3. COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
  4. Extracellular release in the quality control of the mammalian mitochondria.
  5. Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
  6. PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.
  7. Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
  8. Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase.
  9. Targeting mitochondrial quality control for diabetic cardiomyopathy: Therapeutic potential of hypoglycemic drugs.
  10. FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
  11. Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
  12. Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
  13. Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
  14. The functional significance of mitochondrial respiratory chain supercomplexes.
  15. PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
  1. Sci Adv. 2023 Oct 13. 9(41): eadi1411
    Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
    Raz Bar-Ziv, Naibedya Dutta, Adam Hruby, Edward Sukarto, Maxim Averbukh, Athena Alcala, Hope R Henderson, Jenni Durieux, Sarah U Tronnes, Qazi Ahmad, Theodore Bolas, Joel Perez, Julian G Dishart, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Andrew Dillin.
      The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPRMT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.
    DOI:  https://doi.org/10.1126/sciadv.adi1411
  2. J Mol Med (Berl). 2023 Oct 10.
    Dual roles of UPRer and UPRmt in neurodegenerative diseases.
    Si Xu, Haihui Liu, Chen Wang, Yu Deng, Bin Xu, Tianyao Yang, Wei Liu.
      The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPRer) and the mitochondrial unfolded protein response (UPRmt) in the development of several neurodegenerative diseases.
    Keywords:  Endoplasmic reticulum; Mitochondrion; Neurodegenerative diseases; Unfolded protein responses
    DOI:  https://doi.org/10.1007/s00109-023-02382-9
  3. Nat Metab. 2023 Oct 09.
    COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
    Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.
      Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.
    DOI:  https://doi.org/10.1038/s42255-023-00904-w
  4. J Biomed Sci. 2023 Oct 08. 30(1): 85
    Extracellular release in the quality control of the mammalian mitochondria.
    Kuei-Hsiang Pan, Hung Chang, Wei Yuan Yang.
      Mammalian cells release a wealth of materials to their surroundings. Emerging data suggest these materials can even be mitochondria with perturbed morphology and aberrant function. These dysfunctional mitochondria are removed by migrating cells through membrane shedding. Neuronal cells, cardiomyocytes, and adipocytes send dysfunctional mitochondria into the extracellular space for nearby cells to degrade. Various studies also indicate that there is an interplay between intracellular mitochondrial degradation pathways and mitochondrial release in handling dysfunctional mitochondria. These observations, in aggregate, suggest that extracellular release plays a role in quality-controlling mammalian mitochondria. Future studies will help delineate the various types of molecular machinery mammalian cells use to release dysfunctional mitochondria. Through the studies, we will better understand how mammalian cells choose between intracellular degradation and extracellular release for the quality control of mitochondria.
    Keywords:  Autophagy; Extracellular vesicles; Mitochondria; Mitophagy; Organelle quality control
    DOI:  https://doi.org/10.1186/s12929-023-00979-3
  5. Brain. 2023 Oct 07. pii: awad340. [Epub ahead of print]
    Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
    Camilla Aurora Franchino, Martina Brughera, Valentina Baderna, Daniele De Ritis, Alessandra Rocco, Sara Seneca, Luc Regal, Paola Podini, Maurizio D'Antonio, Camilo Toro, Angelo Quattrini, Emmanuel Scalais, Francesca Maltecca.
      AFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane (IMM). Heterozygous AFG3L2 mutations cause Spinocerebellar Ataxia type 28 (SCA28) or Dominant Optic Atrophy type 12 (DOA12), while biallelic AFG3L2 mutations result in the rare and severe Spastic Ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia, and myoclonic epilepsy. We previously reported that the absence or mutation of AFG3L2 leads to the accumulation of mitochondria-encoded proteins, causing the over-activation of the stress-sensitive protease OMA1, which over-processes OPA1, leading to mitochondrial fragmentation. Recently, OMA1 has been identified as the pivotal player communicating mitochondrial stress to the cytosol via a pathway involving the IMM protein DELE1 and the cytosolic kinase HRI, thus eliciting the integrated stress response (ISR). In general, the ISR reduces global protein synthesis and drives the expression of cytoprotective genes that allow cells to endure proteotoxic stress. However, the relevance of the OMA1-DELE1-HRI axis in vivo, and especially in a human CNS disease context, has been poorly documented so far. In this work, we demonstrated that mitochondrial proteotoxicity in the absence/mutation of AFG3L2 activates the OMA1-DELE1-HRI pathway eliciting the ISR. We indeed found enhanced OMA1-dependent processing of DELE1 upon depletion of AFG3L2. Also, in both skin fibroblasts from SPAX5 patients (including a novel case) and in the cerebellum of Afg3l2-/- mice we detected increased phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α), increased levels of ATF4 and strong upregulation of its downstream targets (Chop, Chac1, Ppp1r15a and Ffg21). Silencing of DELE1 or HRI in SPAX5 fibroblasts (where OMA1 is overactivated at basal state) reduces eIF2α phosphorylation and affects cell growth. In agreement, pharmacological potentiation of ISR via Sephin-1, a drug that selectively inhibits the stress-induced eIF2alpha phosphatase GADD34 (encoded by Ppp1r15a), improved cell growth of SPAX5 fibroblasts, and cell survival and dendritic arborization ex vivo in primary Afg3l2-/- Purkinje neurons (PNs). Notably, Sephin-1 treatment in vivo extended the life span of Afg3l2-/- mice, improved PN morphology, mitochondrial ultrastructure and respiratory capacity. These data indicate that activation of the OMA1-DELE1-HRI pathway is protective in the context of SPAX5. Pharmacological tuning of the ISR may represent a future therapeutic strategy for SPAX5 and other cerebellar ataxias caused by impaired mitochondrial proteostasis.
    Keywords:  OMA1; integrated stress response; spastic ataxia type 5
    DOI:  https://doi.org/10.1093/brain/awad340
  6. Biochem Biophys Res Commun. 2023 Sep 29. pii: S0006-291X(23)01134-8. [Epub ahead of print]682 71-76
    PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.
    Ji Eun Han, Kyong-Hwa Kang, Hyunjin Kim, Young Bin Hong, Byung-Ok Choi, Hyongjong Koh.
      Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones with the α-crystalline domain that is critical to their chaperone activity. Within the sHSP family, three (HSPB1, HSPB3, and HSPB8) proteins are linked with inherited peripheral neuropathies, including distal hereditary motor neuropathy (dHMN) and Charco-Marie-Tooth disease (CMT). In this study, we introduced the HSPB3 Y118H (HSPB3Y118H) mutant gene identified from the CMT2 family in Drosophila. With a missense mutation on its α-crystalline domain, this human HSPB3 mutant gene induced a loss of motor activity accompanied by reduced mitochondrial membrane potential in fly neuronal tissues. Moreover, mitophagy, a critical mechanism of mitochondrial quality control, is downregulated in fly motor neurons expressing HSPB3Y118H. Surprisingly, PINK1 and Parkin, the core regulators of mitophagy, successfully rescued these motor and mitochondrial abnormalities in HSPB3 mutant flies. Results from the first animal model of HSPB3 mutations suggest that mitochondrial dysfunction plays a critical role in HSPB3-associated human pathology.
    Keywords:  Charcot-Marie-Tooth disease; Distal hereditary motor neuropathies; Drosophila; HSPB3; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.bbrc.2023.09.092
  7. J Biomed Sci. 2023 Oct 12. 30(1): 86
    Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
    Lei Liu, Yanjun Li, Guo Chen, Quan Chen.
      Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.
    Keywords:  Aging; Aging-related diseases; Mitochondrial biogenesis; Mitochondrial quality; Mitophagy; Mitophagy receptors
    DOI:  https://doi.org/10.1186/s12929-023-00975-7
  8. Mol Metab. 2023 Oct 10. pii: S2212-8778(23)00150-3. [Epub ahead of print] 101816
    Physical exercise elicits UPRmt in the skeletal muscle: The role of c-Jun N-terminal kinase.
    Rodrigo Stellzer Gaspar, Carlos Kiyoshi Katashima, Barbara Moreira Crisol, Fernanda Silva Carneiro, Igor Sampaio, Leonardo Dos Reis Silveira, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, José Rodrigo Pauli, Eduardo Rochete Ropelle.
       OBJECTIVE: The mitochondrial unfolded protein response (UPRmt) is an adaptive cellular response to stress to ensure mitochondrial proteostasis and function. Here we explore the capacity of physical exercise to induce UPRmt in the skeletal muscle.
    METHODS: Therefore, we combined mouse models of exercise (swimming and treadmill running), pharmacological intervention, and bioinformatics analyses.
    RESULTS: Firstly, RNA sequencing and Western blotting analysis revealed that an acute aerobic session stimulated several mitostress-related genes and protein content in muscle, including the UPRmt markers. Conversely, using a large panel of isogenic strains of BXD mice, we identified that BXD73a and 73b strains displayed low levels of several UPRmt-related genes in the skeletal muscle, and this genotypic feature was accompanied by body weight gain, lower locomotor activity, and aerobic capacity. Finally, we identified that c-Jun N-terminal kinase (JNK) activation was critical in exercise-induced UPRmt in the skeletal muscle since pharmacological JNK pathway inhibition blunted exercise-induced UPRmt markers in mice muscle.
    CONCLUSION: Our findings provide new insights into how exercise triggers mitostress signals toward the oxidative capacity in the skeletal muscle.
    Keywords:  JNK; Mitochondria; Physical exercise; Skeletal muscle; UPR(mt)
    DOI:  https://doi.org/10.1016/j.molmet.2023.101816
  9. Biomed Pharmacother. 2023 Oct 09. pii: S0753-3322(23)01467-1. [Epub ahead of print]168 115669
    Targeting mitochondrial quality control for diabetic cardiomyopathy: Therapeutic potential of hypoglycemic drugs.
    Yutong Zhou, Wendong Suo, Xinai Zhang, Jiaojiao Liang, Weizhe Zhao, Yue Wang, Hong Li, Qing Ni.
      Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.
    Keywords:  DPP4i; Diabetic cardiomyopathy; GLP1-RA; Mitochondrial quality control; SGLT2i
    DOI:  https://doi.org/10.1016/j.biopha.2023.115669
  10. Nat Commun. 2023 10 10. 14(1): 6344
    FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
    Jiamin Qiu, Feng Yue, Peipei Zhu, Jingjuan Chen, Fan Xu, Lijia Zhang, Kun Ho Kim, Madigan M Snyder, Nanjian Luo, Hao-Wei Xu, Fang Huang, W Andy Tao, Shihuan Kuang.
      Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
    DOI:  https://doi.org/10.1038/s41467-023-41988-y
  11. Int J Mol Sci. 2023 Sep 22. pii: 14421. [Epub ahead of print]24(19):
    Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
    Hariprasath Ragupathy, Manasvi Vukku, Sandeep Kumar Barodia.
      Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.
    Keywords:  astrocytes; microglia; mitochondria; neurons; oligodendrocytes; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241914421
  12. Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]
    Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
    Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.
      Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.
    Keywords:  ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.026
  13. EMBO Rep. 2023 Oct 11. e57228
    Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
    Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.
      Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
    Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines
    DOI:  https://doi.org/10.15252/embr.202357228
  14. EMBO Rep. 2023 Oct 12. e57092
    The functional significance of mitochondrial respiratory chain supercomplexes.
    Andreas Kohler, Antoni Barrientos, Flavia Fontanesi, Martin Ott.
      The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.
    Keywords:  Mitochondria; bioenergetics; electron transfer; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.15252/embr.202357092
  15. Nat Commun. 2023 Oct 13. 14(1): 6431
    PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
    Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.
      PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
    DOI:  https://doi.org/10.1038/s41467-023-42069-w
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