bims-mitpro Biomed News
on Mitochondrial proteostasis
Issue of 2023–08–20
thirteen papers selected by
Andreas Kohler, University of Graz
  1. A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of T. brucei.
  2. FAM210A mediates an inter-organelle crosstalk essential for protein synthesis and muscle growth in mouse.
  3. Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.
  4. PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.
  5. E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.
  6. NLRX1: versatile functions of a mitochondrial NLR protein that controls mitophagy.
  7. Two conformations of the Tom20 preprotein receptor in the TOM holo complex.
  8. Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.
  9. Control of mitochondrial integrity influences oocyte quality during reproductive aging.
  10. The mitophagy pathway and its implications in human diseases.
  11. When mitophagy dictates the outcome of cellular infection: the case of Brucella abortus.
  12. Study on the Role of Mitophagy Receptor PHB2 in Doubly Uniparental Inheritance of Hyriopsis cumingii.
  13. The diversified role of mitochondria in ferroptosis in cancer.
  1. Life Sci Alliance. 2023 Nov;pii: e202302004. [Epub ahead of print]6(11):
    A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of T. brucei.
    Markus Gerber, Ida Suppanz, Silke Oeljeklaus, Moritz Niemann, Sandro Käser, Bettina Warscheid, André Schneider, Caroline E Dewar.
      The AAA-ATPase Msp1 extracts mislocalised outer membrane proteins and thus contributes to mitochondrial proteostasis. Using pulldown experiments, we show that trypanosomal Msp1 localises to both glycosomes and the mitochondrial outer membrane, where it forms a complex with four outer membrane proteins. The trypanosome-specific pATOM36 mediates complex assembly of α-helically anchored mitochondrial outer membrane proteins such as protein translocase subunits. Inhibition of their assembly triggers a pathway that results in the proteasomal digestion of unassembled substrates. Using inducible single, double, and triple RNAi cell lines combined with proteomic analyses, we demonstrate that not only Msp1 but also the trypanosomal homolog of the AAA-ATPase VCP are implicated in this quality control pathway. Moreover, in the absence of VCP three out of the four Msp1-interacting mitochondrial proteins are required for efficient proteasomal digestion of pATOM36 substrates, suggesting they act in concert with Msp1. pATOM36 is a functional analog of the yeast mitochondrial import complex complex and possibly of human mitochondrial animal-specific carrier homolog 2, suggesting that similar mitochondrial quality control pathways linked to Msp1 might also exist in yeast and humans.
    DOI:  https://doi.org/10.26508/lsa.202302004
  2. bioRxiv. 2023 Aug 05. pii: 2023.08.03.551853. [Epub ahead of print]
    FAM210A mediates an inter-organelle crosstalk essential for protein synthesis and muscle growth in mouse.
    Jingjuan Chen, Feng Yue, Kun Ho Kim, Peipei Zhu, Jiamin Qiu, W Andy Tao, Shihuan Kuang.
      Mitochondria are not only essential for energy production in eukaryocytes but also a key regulator of intracellular signaling. Here, we report an unappreciated role of mitochondria in regulating cytosolic protein translation in skeletal muscle cells (myofibers). We show that the expression of mitochondrial protein FAM210A (Family With Sequence Similarity 210 Member A) is positively associated with muscle mass in mice and humans. Muscle-specific Myl1 Cre -driven Fam210a knockout ( Fam210a MKO ) in mice reduces mitochondrial density and function, leading to progressive muscle atrophy and premature death. Metabolomic and biochemical analyses reveal that Fam210a MKO reverses the oxidative TCA cycle towards the reductive direction, resulting in acetyl-CoA accumulation and hyperacetylation of cytosolic proteins. Specifically, hyperacetylation of several ribosomal proteins leads to disassembly of ribosomes and translational defects. Transplantation of Fam210a MKO mitochondria into wildtype myoblasts is sufficient to elevate protein acetylation in recipient cells. These findings reveal a novel crosstalk between the mitochondrion and ribosome mediated by FAM210A.
    DOI:  https://doi.org/10.1101/2023.08.03.551853
  3. Nat Commun. 2023 Aug 18. 14(1): 5031
    Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.
    Wenjing Liang, Shakti Sagar, Rishith Ravindran, Rita H Najor, Justin M Quiles, Liguo Chi, Rachel Y Diao, Benjamin P Woodall, Leonardo J Leon, Erika Zumaya, Jason Duran, David M Cauvi, Antonio De Maio, Eric D Adler, Åsa B Gustafsson.
      Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.
    DOI:  https://doi.org/10.1038/s41467-023-40680-5
  4. Front Pharmacol. 2023 ;14 1220620
    PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.
    Alessia Di Donfrancesco, Christian Berlingieri, Marta Giacomello, Chiara Frascarelli, Ana Paula Magalhaes Rebelo, Laurence A Bindoff, Segel Reeval, Paul Renbaum, Filippo M Santorelli, Giulia Massaro, Carlo Viscomi, Massimo Zeviani, Daniele Ghezzi, Emanuela Bottani, Dario Brunetti.
      Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of PITRM1) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists. Methods: We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients' fibroblasts, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis. Results: We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Discussion: Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.
    Keywords:  cerebellar ataxia; mitochondrial disease; neurodegenaration; pioglitazone; proteostasis
    DOI:  https://doi.org/10.3389/fphar.2023.1220620
  5. Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00563-4. [Epub ahead of print]83(16): 2976-2990.e9
    E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.
    Vincent Anton, Ira Buntenbroich, Tânia Simões, Mariana Joaquim, Leonie Müller, Reinhard Buettner, Margarete Odenthal, Thorsten Hoppe, Mafalda Escobar-Henriques.
      Ubiquitin-dependent control of mitochondrial dynamics is important for protein quality and neuronal integrity. Mitofusins, mitochondrial fusion factors, can integrate cellular stress through their ubiquitylation, which is carried out by multiple E3 enzymes in response to many different stimuli. However, the molecular mechanisms that enable coordinated responses are largely unknown. Here we show that yeast Ufd2, a conserved ubiquitin chain-elongating E4 enzyme, is required for mitochondrial shape adjustments. Under various stresses, Ufd2 translocates to mitochondria and triggers mitofusin ubiquitylation. This elongates ubiquitin chains on mitofusin and promotes its proteasomal degradation, leading to mitochondrial fragmentation. Ufd2 and its human homologue UBE4B also target mitofusin mutants associated with Charcot-Marie-Tooth disease, a hereditary sensory and motor neuropathy characterized by progressive loss of the peripheral nerves. This underscores the pathophysiological importance of E4-mediated ubiquitylation in neurodegeneration. In summary, we identify E4-dependent mitochondrial stress adaptation by linking various metabolic processes to mitochondrial fusion and fission dynamics.
    Keywords:  CMT2A; Cdc48/p97; E4; Fzo1; MFN2; UBE4B; Ufd2; fusion; mitochondria; mitofusin; stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.021
  6. Biomed J. 2023 Aug 11. pii: S2319-4170(23)00072-0. [Epub ahead of print] 100635
    NLRX1: versatile functions of a mitochondrial NLR protein that controls mitophagy.
    Paul Y Bi, Samuel A Killackey, Linus Schweizer, Stephen E Girardin.
      NLRX1 is a member of the of the Nod-like receptor (NLR) family, and it represents a unique pattern recognition molecule (PRM) as it localizes to the mitochondrial matrix in resting conditions. Over the past fifteen years, NLRX1 has been proposed to regulate multiple cellular processes, including antiviral immunity, apoptosis, reactive oxygen species (ROS) generation and mitochondrial metabolism. Similarly, in vivo models have shown that NLRX1 was associated with the control of a number of diseases, including multiple sclerosis, colorectal cancer and ischemia-reperfusion injury. This apparent versatility in function hinted that a common and general overarching role for NLRX1 may exist. Recent evidence has suggested that NLRX1 controls mitophagy through the detection of a specific "danger signal", namely the defective import of proteins into mitochondria, or mitochondrial protein import stress (MPIS). In this review article, we propose that mitophagy regulation may represent the overarching process detected by NLRX1, which could in turn impact on a number of diseases if dysfunctional.
    DOI:  https://doi.org/10.1016/j.bj.2023.100635
  7. Proc Natl Acad Sci U S A. 2023 08 22. 120(34): e2301447120
    Two conformations of the Tom20 preprotein receptor in the TOM holo complex.
    Pamela Ornelas, Thomas Bausewein, Janosch Martin, Nina Morgner, Stephan Nussberger, Werner Kühlbrandt.
      The TOM complex is the main entry point for precursor proteins (preproteins) into mitochondria. Preproteins containing targeting sequences are recognized by the TOM complex and imported into mitochondria. We have determined the structure of the TOM core complex from Neurospora crassa by single-particle electron cryomicroscopy at 3.3 Å resolution, showing its interaction with a bound preprotein at 4 Å resolution, and of the TOM holo complex including the Tom20 receptor at 6 to 7 Å resolution. TOM is a transmembrane complex consisting of two β-barrels, three receptor subunits, and three short transmembrane subunits. Tom20 has a transmembrane helix and a receptor domain on the cytoplasmic side. We propose that Tom20 acts as a dynamic gatekeeper, guiding preproteins into the pores of the TOM complex. We analyze the interactions of Tom20 with other TOM subunits, present insights into the structure of the TOM holo complex, and suggest a translocation mechanism.
    Keywords:  TOM complex; Tom20; cryoEM; translocation
    DOI:  https://doi.org/10.1073/pnas.2301447120
  8. Mol Neurobiol. 2023 Aug 18.
    Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.
    Renu A Kowluru, Ghulam Mohammad, Jay Kumar.
      Retinopathy fails to halt even after diabetic patients in poor glycemic control try to institute tight glycemic control, suggesting a "metabolic memory" phenomenon, and the experimental models have demonstrated that mitochondria continue to be damaged/dysfunctional, fueling into the vicious cycle of free radicals. Our aim was to investigate the role of removal of the damaged mitochondria in the metabolic memory. Using human retinal endothelial cells (HRECs), incubated in 20 mM D-glucose for 4 days, followed by 5 mM D-glucose for 4 additional days, mitochondrial turnover, formation of mitophagosome, and mitophagy flux were evaluated. Mitophagy was confirmed in a rat model of metabolic memory where the rats were kept in poor glycemic control (blood glucose ~ 400 mg/dl) for 3 months soon after induction of streptozotocin-induced diabetes, followed by 3 additional months of good control (BG < 150 mg/dl). Reversal of high glucose by normal glucose had no effect on mitochondrial turnover and mitophagosome formation, and mitophagy flux remained compromised. Similarly, 3 months of good glycemic control in rats, which had followed 3 months of poor glycemic control, had no effect on mitophagy flux. Thus, poor turnover/removal of the damaged mitochondria, initiated during poor glycemic control, does not benefit from the termination of hyperglycemic insult, and the damaged mitochondria continue to produce free radicals, suggesting the importance of mitophagy in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy.
    Keywords:  Diabetes; Metabolic memory; Mitochondria; Mitophagy; Retinopathy
    DOI:  https://doi.org/10.1007/s12035-023-03534-1
  9. Mol Hum Reprod. 2023 Aug 18. pii: gaad028. [Epub ahead of print]
    Control of mitochondrial integrity influences oocyte quality during reproductive aging.
    Shaihla A Khan, Laura Reed, William B Schoolcraft, Ye Yuan, Rebecca L Krisher.
      Reduced quality in oocytes from women of advanced maternal age is associated with dysfunctional mitochondria. The objective of this study was to investigate the mechanisms controlling mitochondrial quality during maternal aging in mouse and human oocytes. We first evaluated the expression of proteins involved in the mitochondrial unfolded protein response (UPRmt) and mitophagy in in-vivo matured metaphase II oocytes collected from young and aged mice. Expression of UPRmt proteins, HSPD1 and LONP1, and mitophagy proteins, total-PRKN and phosphorylated-PRKN, was significantly decreased in aged compared to young oocytes. Treatment of aged oocytes during in-vitro maturation with the mitochondrially targeted antioxidant mitoquinone (MQ) specifically restored total-PRKN and phosphorylated-PRKN expression to levels seen in young oocytes. We next investigated whether maturing young oocytes under a high oxygen environment would mimic the effects observed in oocytes from aged females. Phosphorylated-PRKN expression in oxidatively stressed young oocytes was reduced compared to that in oocytes matured under normal oxygen levels and the mitochondrial DNA (mtDNA) copy number was increased. Treating oxidatively challenged young oocytes with MQ restored the phosphorylated-PRKN expression and mtDNA copy numbers. Treatment of oxidatively challenged oocytes with MQ also increased the co-localization of mitochondria and lysosomes, suggesting increased mitophagy. These data correlated with the developmental potential of the oocytes, as blastocyst development and hatching of oxidatively stressed oocytes was reduced, while treatment with MQ resulted in a significant increase in blastocyst development and hatching, and in the percentage of inner cell mass. Consistent with our results in mice, metaphase II oocytes from women of advanced maternal age exhibited a significant decrease in phosphorylated-PKRN and total-PRKN compared to those of young women. Our findings suggest that the protein machinery to control the health of the mitochondria via UPRmt and mitophagy may be compromised in oocytes from aged females, which may result in inefficient clearance of dysfunctional mitochondria and reduced oocyte quality.
    Keywords:  advanced maternal age; mitochondria; mitochondrial unfolded protein response; mitophagy; oocyte
    DOI:  https://doi.org/10.1093/molehr/gaad028
  10. Signal Transduct Target Ther. 2023 08 16. 8(1): 304
    The mitophagy pathway and its implications in human diseases.
    Shouliang Wang, Haijiao Long, Lianjie Hou, Baorong Feng, Zihong Ma, Ying Wu, Yu Zeng, Jiahao Cai, Da-Wei Zhang, Guojun Zhao.
      Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.
    DOI:  https://doi.org/10.1038/s41392-023-01503-7
  11. Autophagy. 2023 Aug 17. 1-2
    When mitophagy dictates the outcome of cellular infection: the case of Brucella abortus.
    Jérémy Verbeke, Xavier De Bolle, Thierry Arnould.
      Mitochondria are at the basis of various cellular functions ranging from metabolism and redox homeostasis to inflammation and cell death regulation. Mitochondria therefore constitute an attractive target for invading pathogens to fulfil their infectious cycle. This involves the modulation to their advantage of mitochondrial metabolism and dynamics, including the controlled degradation of mitochondria through mitophagy. Mitophagy might for instance be beneficial for bacterial survival as it can clear bactericidal mitochondrial ROS produced by damaged organelle fragments from the intracellular niche. In the case of the bacterial pathogen Brucella abortus, mitophagy induction has another role in the intracellular lifecycle of the bacteria. Indeed, in our study, we showed that B. abortus triggers an iron-dependent BNIP3L-mediated mitophagy response required for proper bacterial egress and infection of neighboring cells. These results highlight the diversity of mitophagy processes that might be crucial for several stages of cellular infection.
    Keywords:  BNIP3L; Brucella; HIF1A; intracellular trafficking; iron; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2246354
  12. Mar Biotechnol (NY). 2023 Aug 18.
    Study on the Role of Mitophagy Receptor PHB2 in Doubly Uniparental Inheritance of Hyriopsis cumingii.
    Yayu Wang, Xiaoyue Zhu, Yang Gu, Zongyu Liu, Yingrui Mao, Xiaojun Liu, Zhiyi Bai, Guiling Wang, Jiale Li.
      In bivalves, the heterogeneity of mitochondrial DNA and its unique mode of transmission have been the focus of attention, which is called doubly uniparental inheritance (DUI). Prohibitin-2 (phb2) is a mitochondrial inner membrane protein that is a key mitophagy receptor for parental mitochondrial removal. Hyriopsis cumingii is a freshwater bivalve in China, the full-length cDNA of H. cumingii phb2 (named Hcphb2) is 2917 bp and encodes a total of 300 amino acids, a highly conserved sequence. Hcphb2 was highly expressed in the ovary. In the gonadal tissues of 5- to 8-month-old female mussels, the expression level of Hcphb2 continued to significantly increase. After Hcphb2 siRNA interference in 6-month-old female mussels, the expression of M-COII, a marker gene on M-type mitochondria, showed a considerable increase (p < 0.05). In contrast, the expression of autophagosome formation and maturation-related genes, atg4b, atg5, atg12, and atg16l, in the ATG family genes was significantly decreased (p < 0.01). Subcellular localization showed that Hcphb2 appeared in spermatogonia, spermatocyte, spermatid, and sperm, and its location changes synchronize with the behavior of M-type mitochondria location changes in DUI species. And it was found that miR-184 negatively regulated Hcphb2. The above results suggest that the mitochondrial autophagy receptor gene Hcphb2 may be associated with the degradation of M-type mitochondria in the freshwater mussel. This process requires multiple genes to participate, of which Hcphb2 and autophagy genes are only some of those that may play a role.
    Keywords:  Autophagy; Doubly uniparental inheritance; M-type mitochondria; Phb2; miR-184
    DOI:  https://doi.org/10.1007/s10126-023-10240-5
  13. Cell Death Dis. 2023 08 14. 14(8): 519
    The diversified role of mitochondria in ferroptosis in cancer.
    Yu'e Liu, Shiping Lu, Lei-Lei Wu, Liang Yang, Lixue Yang, Jinghan Wang.
      Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by iron overload and ROS accumulation, ferroptosis is modulated by various cellular metabolic and signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, the DHODH-CoQH2 system and the sex hormones suppress ferroptosis. Mitochondrial iron metabolism regulates ferroptosis and mitochondria also undergo a morphological change during ferroptosis, these changes include increased membrane density and reduced mitochondrial cristae. Moreover, mitochondrial energy metabolism changes during ferroptosis, the increased oxidative phosphorylation and ATP production rates lead to a decrease in the glycolysis rate. In addition, excessive oxidative stress induces irreversible damage to mitochondria, diminishing organelle integrity. ROS production, mitochondrial membrane potential, mitochondrial fusion and fission, and mitophagy also function in ferroptosis. Notably, some ferroptosis inhibitors target mitochondria. Ferroptosis is a major mechanism for cell death associated with the progression of cancer. Metastasis-prone or metastatic cancer cells are more susceptible to ferroptosis. Inducing ferroptosis in tumor cells shows very promising potential for treating drug-resistant cancers. In this review, we present a brief retrospect of the discovery and the characteristics of ferroptosis, then we discuss the regulation of ferroptosis and highlight the unique role played by mitochondria in the ferroptosis of cancer cells. Furthermore, we explain how ferroptosis functions as a double-edged sword as well as novel therapies aimed at selectively manipulating cell death for cancer eradication.
    DOI:  https://doi.org/10.1038/s41419-023-06045-y
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