bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023–11–12
nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
  2. Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
  3. A review for the correlation between optic atrophy 1-dependent mitochondrial fusion and cardiovascular disorders.
  4. Mitohormesis.
  5. NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.
  6. Mitophagy Activation by Urolithin A to Target Muscle Aging.
  7. Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects.
  8. Mitochondrial AAA+ proteases.
  9. Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease.
  1. Life Sci Alliance. 2024 Jan;pii: e202302335. [Epub ahead of print]7(1):
    ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
    Alexandre Janer, Jordan L Morris, Michiel Krols, Hana Antonicka, Mari J Aaltonen, Zhen-Yuan Lin, Hanish Anand, Anne-Claude Gingras, Julien Prudent, Eric A Shoubridge.
      Mitochondria interact with the ER at structurally and functionally specialized membrane contact sites known as mitochondria-ER contact sites (MERCs). Combining proximity labelling (BioID), co-immunoprecipitation, confocal microscopy and subcellular fractionation, we found that the ER resident SMP-domain protein ESYT1 was enriched at MERCs, where it forms a complex with the outer mitochondrial membrane protein SYNJ2BP. BioID analyses using ER-targeted, outer mitochondrial membrane-targeted, and MERC-targeted baits, confirmed the presence of this complex at MERCs and the specificity of the interaction. Deletion of ESYT1 or SYNJ2BP reduced the number and length of MERCs. Loss of the ESYT1-SYNJ2BP complex impaired ER to mitochondria calcium flux and provoked a significant alteration of the mitochondrial lipidome, most prominently a reduction of cardiolipins and phosphatidylethanolamines. Both phenotypes were rescued by reexpression of WT ESYT1 and an artificial mitochondria-ER tether. Together, these results reveal a novel function for ESYT1 in mitochondrial and cellular homeostasis through its role in the regulation of MERCs.
    DOI:  https://doi.org/10.26508/lsa.202302335
  2. EMBO J. 2023 Nov 07. e114054
    Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
    Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Daniel Milshteyn, Guy Perkins, Keun-Young Kim, H Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark H Ellisman, Padmini Rangamani, Itay Budin.
      Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.
    Keywords:  cardiolipin; cristae; lipids; mechanics; mitochondria
    DOI:  https://doi.org/10.15252/embj.2023114054
  3. Int J Biol Macromol. 2023 Nov 06. pii: S0141-8130(23)04809-2. [Epub ahead of print]254(Pt 2): 127910
    A review for the correlation between optic atrophy 1-dependent mitochondrial fusion and cardiovascular disorders.
    Bi-Feng Yao, Xiu-Ju Luo, Jun Peng.
      Mitochondrial dynamics homeostasis is sustained by continuous and balanced fission and fusion, which are determinants of morphology, abundance, biogenesis and mitophagy of mitochondria. Optic atrophy 1 (OPA1), as the only inner mitochondrial membrane fusion protein, plays a key role in stabilizing mitochondrial dynamics. The disturbance of mitochondrial dynamics contributes to the pathophysiological progress of cardiovascular disorders, which are the main cause of death worldwide in recent decades and result in tremendous social burden. In this review, we describe the latest findings regarding OPA1 and its role in mitochondrial fusion. We summarize the post-translational modifications (PTMs) for OPA1 and its regulatory role in mitochondrial dynamics. Then the diverse cell fates caused by OPA1 expression during cardiovascular disorders are discussed. Moreover, cardiovascular disorders (such as heart failure, myocardial ischemia/reperfusion injury, cardiomyopathy and cardiac hypertrophy) relevant to OPA1-dependent mitochondrial dynamics imbalance have been detailed. Finally, we highlight the potential that targeting OPA1 to impact mitochondrial fusion may be used as a novel strategy against cardiovascular disorders.
    Keywords:  Cardiovascular disorders; Cell death; Mitochondrial dynamics; Optic atrophy 1; Post-translation modification
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127910
  4. Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00380-7. [Epub ahead of print]35(11): 1872-1886
    Mitohormesis.
    Yu-Wei Cheng, Jie Liu, Toren Finkel.
      Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.011
  5. J Cell Physiol. 2023 Nov 09.
    NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.
    Anbo Gao, Mengjie Wang, Xing Tang, Gangqing Shi, Kai Hou, Jinren Fang, Linlin Zhou, Hong Zhou, Weimin Jiang, Yukun Li, Fan Ouyang.
      Radiation-induced heart damage caused by low-dose X-rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL-IN-1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification-based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low-dose X-rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co-IP coupled with LC-MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2-mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.
    Keywords:  MUL1; NDP52; PINK1/Parkin; SUMOylation; mitophagy; radiation-induced heart damage
    DOI:  https://doi.org/10.1002/jcp.31145
  6. Calcif Tissue Int. 2023 Nov 05.
    Mitophagy Activation by Urolithin A to Target Muscle Aging.
    Julie Faitg, Davide D'Amico, Chris Rinsch, Anurag Singh.
      The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.
    Keywords:  Aging; Mitochondria; Mitophagy; Muscle health; Urolithin A
    DOI:  https://doi.org/10.1007/s00223-023-01145-5
  7. Sci Bull (Beijing). 2023 Oct 26. pii: S2095-9273(23)00721-1. [Epub ahead of print]
    Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects.
    Shuixia Tan, Da Wang, Yuhua Fu, Huiwen Zheng, Yan Liu, Boxun Lu.
      Increased mitochondrial damage plays a critical role in many neurodegeneration-related diseases such as Parkinson's disease (PD) and Down syndrome (DS). Thus, enhancement of mitochondrial degradation by small molecule compounds may provide promising new strategies to tackle these diseases. Here, we explored the strategy to induce clearance of mitochondria by targeting them to the autophagy machinery by autophagy-tethering compounds (ATTECs). We provided the proof-of-concept evidence demonstrating that the bifunctional compound (mT1) binding to both the outer mitochondrial membrane protein TSPO and the autophagosome protein LC3B simultaneously may enhance the engulfment of damaged mitochondria by autophagosomes and subsequent autophagic degradation of them. In addition, preliminary experiments suggest that mT1 attenuated disease-relevant phenotypes in both a PD cellular model and a DS organoid model. Taken together, we demonstrate the possibility of degrading mitochondria by bifunctional ATTECs, which confirms the capability of degrading organelles by ATTECs and provides potential new strategies in the intervention of mitochondria-related disorders.
    Keywords:  Autophagy-tethering compounds; Chimera compound; Lysosome; Neurodegenerative diseases; TSPO; Targeted mitochondrial degradation
    DOI:  https://doi.org/10.1016/j.scib.2023.10.021
  8. Enzymes. 2023 ;pii: S1874-6047(23)00028-8. [Epub ahead of print]54 205-220
    Mitochondrial AAA+ proteases.
    Yuichi Matsushima.
      Mitochondria are multifunctional organelles that play a central role in a wide range of life-sustaining tasks in eukaryotic cells, including adenosine triphosphate (ATP) production, calcium storage and coenzyme generation pathways such as iron-sulfur cluster biosynthesis. The wide range of mitochondrial functions is carried out by a diverse array of proteins comprising approximately 1500 proteins or polypeptides. Degradation of these proteins is mainly performed by four AAA+ proteases localized in mitochondria. These AAA+ proteases play a quality control role in degrading damaged or misfolded proteins and perform various other functions. This chapter describes previously identified roles for these AAA+ proteases that are localized in the mitochondria of animal cells.
    Keywords:  AAA+ protease; ClpXP; Lon; Mitochondria; i-AAA; m-AAA
    DOI:  https://doi.org/10.1016/bs.enz.2023.09.002
  9. Cell Mol Life Sci. 2023 Nov 06. 80(12): 347
    Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease.
    Jia-Ling Ji, Jun-Ying Li, Jian-Xiang Liang, Yan Zhou, Cong-Cong Liu, Yao Zhang, Ai-Qing Zhang, Hong Liu, Rui-Xia Ma, Zuo-Lin Li.
      Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca2+-activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. Mechanically, TMEM16A mediated tubular mitochondrial dysfunction through inhibiting PGC-1α, whereas overexpression of PGC-1α could rescue the changes. In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl-, and reducing intracellular Cl- significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. Blockade of TMEM16A may serve as a novel therapeutic approach to ameliorate TIF.
    Keywords:  Intracellular Cl−; Mitochondrial dysfunction; PGC-1α; TMEM16A; Tubulointerstitial fibrosis
    DOI:  https://doi.org/10.1007/s00018-023-05000-6
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