bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023‒10‒22
sixteen papers selected by
Gavin McStay, Liverpool John Moores University
  1. mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.
  2. High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.
  3. Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
  4. Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage.
  5. The novel cyclophilin inhibitor C105SR reduces hepatic ischaemia-reperfusion injury via mitoprotection.
  6. A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.
  7. Targeting mitochondrial degradation by chimeric autophagy-tethering compounds.
  8. Mitophagy in neurodegenerative disease pathogenesis.
  9. StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.
  10. MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.
  11. GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney aging.
  12. Mitophagy in yeast: known unknowns and unknown unknowns.
  13. Control of mitochondrial dynamics by a fusogenic lipid.
  14. Zinc Overload Induces Damage to H9c2 Cardiomyocyte Through Mitochondrial Dysfunction and ROS-Mediated Mitophagy.
  15. FUNDC1/PFKP-mediated mitophagy induced by KD025 ameliorates cartilage degeneration in osteoarthritis.
  16. Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in platelets.
  1. Nucleic Acids Res. 2023 Oct 18. pii: gkad864. [Epub ahead of print]
    mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.
    Timo Rey, Luis Carlos Tábara, Julien Prudent, Michal Minczuk.
      Mitochondrial DNA (mtDNA) encodes the core subunits for OXPHOS, essential in near-all eukaryotes. Packed into distinct foci (nucleoids) inside mitochondria, the number of mtDNA copies differs between cell-types and is affected in several human diseases. Currently, common protocols estimate per-cell mtDNA-molecule numbers by sequencing or qPCR from bulk samples. However, this does not allow insight into cell-to-cell heterogeneity and can mask phenotypical sub-populations. Here, we present mtFociCounter, a single-cell image analysis tool for reproducible quantification of nucleoids and other foci. mtFociCounter is a light-weight, open-source freeware and overcomes current limitations to reproducible single-cell analysis of mitochondrial foci. We demonstrate its use by analysing 2165 single fibroblasts, and observe a large cell-to-cell heterogeneity in nucleoid numbers. In addition, mtFociCounter quantifies mitochondrial content and our results show good correlation (R = 0.90) between nucleoid number and mitochondrial area, and we find nucleoid density is less variable than nucleoid numbers in wild-type cells. Finally, we demonstrate mtFociCounter readily detects differences in foci-numbers upon sample treatment, and applies to Mitochondrial RNA Granules and superresolution microscopy. mtFociCounter provides a versatile solution to reproducibly quantify cellular foci in single cells and our results highlight the importance of accounting for cell-to-cell variance and mitochondrial context in mitochondrial foci analysis.
    DOI:  https://doi.org/10.1093/nar/gkad864
  2. Appl Physiol Nutr Metab. 2023 Oct 18.
    High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.
    James Tincknell, Benjamin Kugler, Haley Spicuzza, Nicolas Berger, Huimin Yan, Tongjian You, Kai Zou.
      Mitochondrial quality control processes are essential in governing mitochondrial integrity and function. The purpose of the study was to examine the effects of 10 weeks of HIIT on the regulatory protein machinery of skeletal muscle mitochondrial quality control and whole-body glucose homeostasis in diet-induced obese mice. Male C57BL/6 mice were assigned to low-fat diet (LFD) or high-fat diet (HFD) group. After 10 weeks, HFD-fed mice were divided into sedentary and HIIT (HFD+HIIT) groups for another 10 weeks (n=9/group). Graded exercise test, glucose and insulin tolerance tests, mitochondrial respiration and protein markers of mitochondrial quality control processes were determined. HFD-fed mice exhibited lower ADP-stimulated mitochondrial respiration (P<0.05). However, ten weeks of HIIT prevented this impairment (P < 0.05).. Importantly, the ratio of Drp1(Ser616) over Drp1(Ser637) phosphorylation, an indicator of mitochondrial fission, was significantly higher in HFD-fed mice (P<0.05), but such increase was attenuated in HFD-HIIT compared to HFD (-35.7%, P < 0.05). Regarding autophagy, skeletal muscle p62 content was lower in HFD group than LFD group (-35.1%, P < 0.05), however, such reduction was disappeared in HFD+HIIT group. In addition, LC3B II/I ratio was higher in HFD than LFD group (15.5%, P < 0.05) but was ameliorated in HFD+HIIT group (-29.9%, P < 0.05). Overall, our study demonstrated that 10 weeks of HIIT was effective in improving skeletal muscle mitochondrial respiration and the regulatory protein machinery of mitochondrial quality control in diet-induced obese mice through the alterations of mitochondrial fission protein Drp1 phosphorylations and p62/LC3B-mediated regulatory machinery of autophagy.
    DOI:  https://doi.org/10.1139/apnm-2023-0286
  3. Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291
    Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
    Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.
      Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.
    Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113291
  4. Neural Regen Res. 2024 Apr;19(4): 825-832
    Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage.
    Jiatong Zhang, Qi Zhu, Jie Wang, Zheng Peng, Zong Zhuang, Chunhua Hang, Wei Li.
      The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow. Mitochondria are directly affected by direct factors such as ischemia, hypoxia, excitotoxicity, and toxicity of free hemoglobin and its degradation products, which trigger mitochondrial dysfunction. Dysfunctional mitochondria release large amounts of reactive oxygen species, inflammatory mediators, and apoptotic proteins that activate apoptotic pathways, further damaging cells. In response to this array of damage, cells have adopted multiple mitochondrial quality control mechanisms through evolution, including mitochondrial protein quality control, mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer, to maintain mitochondrial homeostasis under pathological conditions. Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage. This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage, particularly mitochondrial quality control mechanisms. It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission and fusion; mitochondrial quality control; mitophagy; subarachnoid hemorrhage
    DOI:  https://doi.org/10.4103/1673-5374.381493
  5. JHEP Rep. 2023 Nov;5(11): 100876
    The novel cyclophilin inhibitor C105SR reduces hepatic ischaemia-reperfusion injury via mitoprotection.
    Amel Kheyar, Nazim Ahnou, Abdelhakim Ahmed-Belkacem, Anne Hulin, Claire Pressiat, Bijan Ghaleh, Jean-François Guichou, Didier Morin, Jean-Michel Pawlotsky, Fatima Teixeira-Clerc.
      Background & Aims: Mitochondrial permeability transition pore (mPTP) opening is critical for mediating cell death during hepatic ischaemia-reperfusion injury (IRI). Blocking mPTP opening by inhibiting cyclophilin D (CypD) is a promising pharmacological approach for the treatment of IRI. Here, we show that diastereoisomers of a new class of small-molecule cyclophilin inhibitors (SMCypIs) have properties that make them attractive candidates for the development of therapeutic agents against liver IRI.Methods: Derivatives of the parent SMCypI were synthesised and evaluated for their ability to inhibit CypD peptidyl-prolyl cis-trans isomerase (PPIase) activity and for their mitoprotective properties, evaluated by measuring mitochondrial swelling and calcium retention capacity in liver mitochondria. The ability of the selected compounds to inhibit mPTP opening was evaluated in cells subjected to hypoxia/reoxygenation using a calcein/cobalt assay. Their ability to inhibit cell death was evaluated in cells subjected to hypoxia/reoxygenation by measuring lactate dehydrogenase (LDH) release, propidium iodide staining, and cell viability. The compound performing best in vitro was selected for in vivo efficacy evaluation in a mouse model of hepatic IRI.
    Results: The two compounds that showed the strongest inhibition of CypD PPIase activity and mPTP opening, C105 and C110, were selected. Their SR diastereoisomers carried the activity of the racemic mixture and exhibited mitoprotective properties superior to those of the known macrocyclic cyclophilin inhibitors cyclosporin A and alisporivir. C105SR was more potent than C110SR in inhibiting mPTP opening and prevented cell death in a model of hypoxia/reoxygenation. Finally, C105SR substantially protected against hepatic IRI in vivo by reducing hepatocyte necrosis and apoptosis.
    Conclusions: We identified a novel cyclophilin inhibitor with strong mitoprotective properties both in vitro and in vivo that represents a promising candidate for cellular protection in hepatic IRI.
    Impact and Implications: Hepatic ischaemia-reperfusion injury (IRI) is one of the main causes of morbidity and mortality during or after liver surgery. However, no effective therapies are available to prevent or treat this devastating syndrome. An attractive strategy to prevent hepatic IRI aims at reducing cell death by targeting mitochondrial permeability transition pore opening, a phenomenon regulated by cyclophilin D. Here, we identified a new small-molecule cyclophilin inhibitor, and demonstrated the enhanced mitoprotective and hepatoprotective properties of one of its diastereoisomers both in vitro and in vivo, making it an attractive lead compound for subsequent clinical development.
    Keywords:  Cellular protection; Liver necrosis; Mitochondrial calcium retention capacity; Mitochondrial permeability transition pore; Mitochondrial swelling; Peptidyl-prolyl cis-trans isomerase activity
    DOI:  https://doi.org/10.1016/j.jhepr.2023.100876
  6. Cell Rep. 2023 Oct 17. pii: S2211-1247(23)01272-X. [Epub ahead of print]42(10): 113260
    A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.
    Christopher S Waters, Sigurd B Angenent, Steven J Altschuler, Lani F Wu.
      Mechanisms that prevent accidental activation of the PINK1/Parkin mitophagy circuit on healthy mitochondria are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria, where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we explore emergent properties of the PINK1/Parkin circuit by quantifying the relationship between mitochondrial PINK1 concentrations and Parkin recruitment dynamics. We find that Parkin is recruited to mitochondria only if PINK1 levels exceed a threshold and then only after a delay that is inversely proportional to PINK1 levels. Furthermore, these two regulatory properties arise from the input-coupled positive feedback topology of the PINK1/Parkin circuit. These results outline an intrinsic mechanism by which the PINK1/Parkin circuit can avoid errant activation on healthy mitochondria.
    Keywords:  CP: Molecular biology; PINK1; Parkin; circuit; delay; mathematical model; mitophagy decision; quantitative microscopy; synthetic biology; systems biology; threshold
    DOI:  https://doi.org/10.1016/j.celrep.2023.113260
  7. Chem Sci. 2023 Oct 18. 14(40): 11192-11202
    Targeting mitochondrial degradation by chimeric autophagy-tethering compounds.
    Zhenqi Liu, Geng Qin, Jie Yang, Wenjie Wang, Wenting Zhang, Boxun Lu, Jinsong Ren, Xiaogang Qu.
      The ability to regulate mitophagy in a living system with small molecules remains a great challenge. We hypothesize that adding fragments specific to the key autophagosome protein LC3 to mitochondria will mimic receptor-mediated mitophagy, thus engaging the autophagy-lysosome pathway to induce mitochondrial degradation. Herein, we develop a general biochemical approach to modulate mitophagy, dubbed mito-ATTECs, which employ chimera molecules composed of LC3-binding moieties linked to mitochondria-targeting ligands. Mito-ATTECs trigger mitophagy via targeting mitochondria to autophagosomes through direct interaction between mito-ATTECs and LC3 on mitochondrial membranes. Subsequently, autophagosomes containing mitochondria rapidly fuse with lysosomes to facilitate the degradation of mitochondria. Therefore, mito-ATTECs circumvent the detrimental effects related to disruption of mitochondrial membrane integrity by inducers routinely used to manipulate mitophagy, and provide a versatile biochemical approach to investigate the physiological roles of mitophagy. Furthermore, we found that sustained mitophagy lead to mitochondrial depletion and autophagic cell death in several malignant cell lines (lethal mitophagy). Among them, apoptosis-resistant malignant melanoma cell lines are particularly sensitive to lethal mitophagy. The therapeutic efficacy of mito-ATTECs has been further evaluated by using subcutaneous and pulmonary metastatic melanoma models. Together, the mitochondrial depletion achieved by mito-ATTECs may demonstrate the general concept of inducing cancer cell lethality through excessive mitochondrial clearance, establishing a promising therapeutic paradigm for apoptosis-resistant tumors.
    DOI:  https://doi.org/10.1039/d3sc03600f
  8. Neural Regen Res. 2024 May;19(5): 998-1005
    Mitophagy in neurodegenerative disease pathogenesis.
    Kan Yang, Yuqing Yan, Anni Yu, Ru Zhang, Yuefang Zhang, Zilong Qiu, Zhengyi Li, Qianlong Zhang, Shihao Wu, Fei Li.
      Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.
    Keywords:  Alzheimer’s disease; PINK1; Parkin; Parkinson’s disease; amyotrophic lateral sclerosis; autophagy; mitochondria; mitophagy; mitophagy receptor
    DOI:  https://doi.org/10.4103/1673-5374.385281
  9. FEBS J. 2023 Oct 16.
    StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.
    María L Rojas, Juan Pablo Muñoz, Jésica Flores-Martín, Paula Sànchez-Fernàndez-de-Landa, Mariano Cruz Del Puerto, Susana Genti-Raimondi, Antonio Zorzano.
      StarD7 is a member of the START protein family required for phosphatidylcholine delivery to the mitochondria, thus key to maintain mitochondrial structure. Its deficiency has been associated with an impairment of cellular processes, such as proliferation and migration, and it has also been reported that it is needed in myogenic differentiation. Here, we show that StarD7 deficiency in C2C12 muscle cells results in the accumulation of abnormal mitochondria, a reduced number of mitochondria per cell area and increased glycolysis. In addition, StarD7-deficient cells undergo an increase in mitochondria-ER contact sites, reduced connexin 43 expression, and disturbances in lipid handling, evidenced by lipid droplet accumulation and decreased levels in phosphatidylserine synthase 1 and 2 expression. Interestingly, StarD7-deficient cells showed alterations in mitophagy markers. We observed accumulation of LC3B-II and BNIP3 proteins in mitochondria-enriched fractions and accumulation of autophagolysosomal and lysosomal vesicles in StarD7-deficient cells. Furthermore, live-cell imaging experiments of StarD7 knockdown cells expressing mitochondria-targeted mKeima indicated an enhanced mitochondria delivery into lysosomes. Importantly, StarD7 reconstitution in StarD7-deficient cells restores LC3B-II expression in mitochondria-enriched fractions at similar levels to those observed in control cells. Collectively, these findings suggest that StarD7-deficient C2C12 myoblasts are associated with altered cristae structure, disturbances in neutral lipid accumulation, glucose metabolism, and increased mitophagy flux. The alterations mentioned above allow for the maintenance of mitochondrial function.
    Keywords:  StarD7; cristae morphology; lipid droplet; mitophagy
    DOI:  https://doi.org/10.1111/febs.16979
  10. Nat Commun. 2023 Oct 14. 14(1): 6493
    MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.
    Yeawon Kim, Chuang Li, Chenjian Gu, Yili Fang, Eric Tycksen, Anuradhika Puri, Terri A Pietka, Jothilingam Sivapackiam, Kendrah Kidd, Sun-Ji Park, Bryce G Johnson, Stanislav Kmoch, Jeremy S Duffield, Anthony J Bleyer, Meredith E Jackrel, Fumihiko Urano, Vijay Sharma, Maria Lindahl, Ying Maggie Chen.
      Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
    DOI:  https://doi.org/10.1038/s41467-023-42154-0
  11. Free Radic Biol Med. 2023 Oct 16. pii: S0891-5849(23)00662-7. [Epub ahead of print]
    GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney aging.
    Li Xu, Jiao Wang, Hongyuan Yu, Hang Mei, Ping He, Min Wang, Yue Liu, Qiuling Fan, Ying Chen, Yanqiu Li, Fan Liu.
      Mitochondrial dysfunction is implied as a crucial factor in age-related chronic kidney disease. It is confirmed that Gli-like transcription factor 1 (GLIS1) is involved in age-related renal fibrosis, however, the correlation between mitochondrial disturbances and GLIS1-driven kidney aging are not clearly clarified. Thus, we investigated the regulatory mechanism of GLIS1 in the homeostasis of mitochondrial quality control both in vivo and in vitro. The lower expression of GLIS1 was identified in natural and accelerated kidney aged models, accompanied by the dysfunctions of mitochondrial quality control, including enhanced mitochondrial fission, reduced mitochondrial biogenesis and mitophagy, whereas, GLIS1 could maintain mitochondrial stability by interacting with peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α). Additionally, the over-expressed GLIS1 inhibited extracellular matrix accumulation and alleviated renal fibrosis while siGLIS1 inhibited PGC1-α transcription, as well as affecting its mitochondria-protective functions. Collectively, we demonstrated that GLIS1 mediated mitochondrial quality control through targeting PGC1-α in kidney aging, which might be a promising therapeutic target for attenuating cell senescence and age-related renal fibrosis.
    Keywords:  GLIS1; Kidney aging; Mitochondrial quality control; PGC1-α; Renal fibrosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.037
  12. Biochem J. 2023 Oct 31. 480(20): 1639-1657
    Mitophagy in yeast: known unknowns and unknown unknowns.
    Hagai Abeliovich.
      Mitophagy, the autophagic breakdown of mitochondria, is observed in eukaryotic cells under various different physiological circumstances. These can be broadly categorized into two types: mitophagy related to quality control events and mitophagy induced during developmental transitions. Quality control mitophagy involves the lysosomal or vacuolar degradation of malfunctioning or superfluous mitochondria within lysosomes or vacuoles, and this is thought to serve as a vital maintenance function in respiring eukaryotic cells. It plays a crucial role in maintaining physiological balance, and its disruption has been associated with the progression of late-onset diseases. Developmentally induced mitophagy has been reported in the differentiation of metazoan tissues which undergo metabolic shifts upon developmental transitions, such as in the differentiation of red blood cells and muscle cells. Although the mechanistic studies of mitophagy in mammalian cells were initiated after the initial mechanistic findings in Saccharomyces cerevisiae, our current understanding of the physiological role of mitophagy in yeast remains more limited, despite the presence of better-defined assays and tools. In this review, I present my perspective on our present knowledge of mitophagy in yeast, focusing on physiological and mechanistic aspects. I aim to focus on areas where our understanding is still incomplete, such as the role of mitochondrial dynamics and the phenomenon of protein-level selectivity.
    Keywords:   Saccharomyces cerevisiae ; autophagy; mitophagy
    DOI:  https://doi.org/10.1042/BCJ20230279
  13. Trends Cell Biol. 2023 Oct 17. pii: S0962-8924(23)00210-6. [Epub ahead of print]
    Control of mitochondrial dynamics by a fusogenic lipid.
    Zheng Yang, David C Chan.
      Mitochondrial fusion enables cooperation between the mitochondrial population and is critical for mitochondrial function. Phosphatidic acid (PA) on the mitochondrial surface has a key role in mitochondrial fusion. A recent study by Su et al. shows that the nucleoside diphosphate (NDP) kinase NME3 recognizes PA and mediates its effects on mitochondrial dynamics.
    Keywords:  membrane fusion; mitochondria; organelle; phospholipid
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.006
  14. Cardiovasc Toxicol. 2023 Dec;23(11-12): 388-405
    Zinc Overload Induces Damage to H9c2 Cardiomyocyte Through Mitochondrial Dysfunction and ROS-Mediated Mitophagy.
    Ying Yang, Pei Wang, Jiabao Guo, Tingting Ma, Youcheng Hu, Luyao Huang, Bohan Xing, Yonggui He, Jinkun Xi.
      Zinc homeostasis is essential for maintaining redox balance, cell proliferation, and apoptosis. However, excessive zinc exposure is toxic and leads to mitochondrial dysfunction. In this study, we established a zinc overload model by treating rat cardiomyocyte H9c2 cells with Zn2+ at different concentrations. Our results showed that zinc overload increased LDH and reactive oxygen species (ROS) levels, leading to cell death, mitochondrial membrane potential decrease and impaired mitochondrial function and dynamics. Furthermore, zinc overload activated the PINK1/Parkin signaling pathway and induced mitochondrial autophagy via ROS, while NAC inhibited mitophagy and weakened the activation of PINK1/Parkin pathway, thereby preserving mitochondrial biogenesis. In addition, our data also showed that Mfn2 deletion increased ROS production and exacerbated cytotoxicity induced by zinc overload. Our results therefore suggest that Zn2+-induced ROS generation causes mitochondrial autophagy and mitochondrial dysfunction, damaging H9c2 cardiomyocytes. Additionally, Mfn2 may play a key role in zinc ion-mediated endoplasmic reticulum and mitochondrial interactions. Our results provide a new perspective on zinc-induced toxicology.
    Keywords:  H9c2; Mitofusin-2; Mitophagy; Reactive oxygen species; Zinc overload
    DOI:  https://doi.org/10.1007/s12012-023-09811-8
  15. Mol Ther. 2023 Oct 13. pii: S1525-0016(23)00557-9. [Epub ahead of print]
    FUNDC1/PFKP-mediated mitophagy induced by KD025 ameliorates cartilage degeneration in osteoarthritis.
    Guibin Fang, Xingzhao Wen, Zongrui Jiang, Xue Du, Ruonan Liu, Chengyun Zhang, Guiwu Huang, Weiming Liao, Zhiqi Zhang.
      Osteoarthritis (OA) is the most common joint disease, but no disease-modifying drugs have been approved for OA treatment. Mitophagy participates in mitochondrial homeostasis regulation by selectively clearing dysfunctional mitochondria, which might contribute to cartilage degeneration in OA. Here, we provide evidence of impaired mitophagy in OA chondrocytes, which exacerbates chondrocyte degeneration. Among the several classic mitophagy-regulating pathways and receptors, we found that FUNDC1 plays a key role in preserving chondrocyte homeostasis by inducing mitophagy. FUNDC1 knockdown in vitro and knockout in vivo decreased mitophagy and exacerbated mitochondrial dysfunction, exacerbating chondrocyte degeneration and OA progression. FUNDC1 overexpression via intra-articular injection of adeno-associated virus alleviated cartilage degeneration in OA. Mechanistically, our study demonstrated that PFKP interacts with and dephosphorylates FUNDC1 to induce mitophagy in chondrocytes. Further analysis identified KD025 as a candidate drug for restoring chondrocyte mitophagy by increasing the FUNDC1- PFKP interaction and thus alleviating cartilage degeneration in mice with DMM-induced OA. Our study highlights the role of the FUNDC1-PFKP interaction in chondrocyte homeostasis via mitophagy induction and identifies KD025 as a promising agent for treating OA by increasing chondrocyte mitophagy.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.10.016
  16. FASEB J. 2023 Nov;37(11): e23239
    Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in platelets.
    Pan Pan, Jie Chen, Fei Xie, Yinghua Guo, Xudong Liu, Dong Zhang, Lixin Xie, Longxiang Su.
      Platelets are highly involved in inflammation and organ injury under pathological conditions. The mitophagy in platelets may restrict hyperactivation of the inflammasome and relieve acute kidney injury (AKI). Cecal ligation puncture (CLP)/LPS-induced AKI Triggering receptor expressed on myeloid cells (TREM-1)-knockout mice models were established. Additionally, septic patients with AKI were also included. TREM-1 expression in platelets and inflammasome activation were examined. Platelet transfer assays were performed to investigate the contribution of platelet TREM-1 to renal injury. Mitophagy was evaluated in the context of inflammation. BNIP3L/Nix knockout mice were used to examine the relationship between platelet mitophagy and inflammatory activation. The results showed that the level of TREM-1 was increased and the platelet inflammasome was hyperactivated in CLP mice and septic patients, and TREM-1 activated platelet inflammasomes. TREM-1 deletion significantly abrogated hyperactivation of the platelet inflammasome and dramatically reduced AKI, whereas ablation of the mitophagy receptor BNIP3L/Nix induced the accumulation of damaged mitochondria and hyperactivation of platelet inflammasomes in CLP mice. BNIP3L/Nix controlled platelet inflammasome activation, and an amplification loop of platelet inflammasome activation and dysfunctional mitochondria controlled sepsis-related AKI. Therefore, targeting TREM-1 and NLRP3/BNIP3L in platelets may represent a novel therapeutic strategy for treating septic AKI.
    Keywords:  BNIP3L/Nix; NLRP3 inflammasome; TREM-1; autophagy; mitochondrion; platelet
    DOI:  https://doi.org/10.1096/fj.202202144RRR
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