bims-tofagi Biomed News
on Mitophagy
Issue of 2025–08–03
eleven papers selected by
Michele Frison, University of Cambridge
  1. Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
  2. Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.
  3. A structural switch reveals how to disarm USP30 and unlock mitophagy.
  4. ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
  5. Rab14 promotes Parkin mediated mitophagy.
  6. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  7. CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
  8. DHRS13 suppresses differentiation and mitophagy in glioma via retinoic acid and mitochondrial reactive oxygen species.
  9. Role of Prohibitins as Guardians of mitochondrial homeostasis.
  10. Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
  11. Urolithin A in Central Nervous System Disorders: Therapeutic Applications and Challenges.
  1. Nat Cell Biol. 2025 Jul 25.
    Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.
    Elias Adriaenssens, Stefan Schaar, Annan S I Cook, Jan F M Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Louise Uoselis, Michael Lazarou, Gerhard Hummer, James H Hurley, Sascha Martens.
      Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with important implications for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41556-025-01712-y
  2. Elife. 2025 Jul 31. pii: RP103945. [Epub ahead of print]14
    Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration.
    Cong Chen, Tong-Yao Gao, Hua-Wei Yi, Yi Zhang, Tong Wang, Zhi-Ling Lou, Tao-Feng Wei, Yun-Bi Lu, Tingting Li, Chun Tang, Wei-Ping Zhang.
      Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.
    Keywords:  PINK1; biochemistry; chemical biology; mouse; neurodegeneration; phosphorylation; proteasome; ubiquitin
    DOI:  https://doi.org/10.7554/eLife.103945
  3. Nat Struct Mol Biol. 2025 Jul 25.
    A structural switch reveals how to disarm USP30 and unlock mitophagy.
    Julia C Fitzgerald, Anja Bremm.
      
    DOI:  https://doi.org/10.1038/s41594-025-01640-3
  4. Cell Death Discov. 2025 Jul 29. 11(1): 349
    ANKZF1 helps to eliminate stress-damaged mitochondria by LC3-mediated mitophagy.
    Mudassar Ali, Anjali, Koyeli Mapa.
      Mitochondria, the double membrane-bound organelles of endosymbiotic origin, are crucial centers for cellular energy production and several essential metabolic pathways. Recent studies reveal that mitochondria become dysfunctional following numerous cellular stresses, and during pathologies, demanding an extensive investigation of mitochondrial turnover mechanisms. Apart from the specific response pathways to tackle different stresses, mitophagy, or degradation of mitochondria by autophagy, is a critical quality control mechanism that clears irreversibly damaged mitochondria. Mitophagy is majorly executed either by receptor-mediated or PINK1-Parkin-dependent pathways. Here, we show that the human orthologue of yeast Vms1, ANKZF1, participates in PINK1-Parkin-mediated mitophagy. We show that ANKZF1 is extensively recruited to damaged mitochondria along with Parkin during mitochondrial proteotoxic stress induced by the expression of a single misfolded/aggregated protein or during uncoupler-induced membrane depolarization. Importantly, ANKZF1 recruitment to damaged mitochondria is significantly enhanced in the presence of Parkin, and ANKZF1 physically interacts with Parkin and LC3 during mitochondrial proteotoxic or depolarization stress. ANKZF1 harbors six putative LC3-interacting regions (LIRs), LIR4 present at residues 333-336, is particularly important for ANKZF1-LC3 interaction. Furthermore, we show that ANKZF1 knockout cells are compromised in clearing stress-damaged mitochondria by mitophagy, indicating an important role of ANKZF1 in mitochondrial turnover during stress. In summary, we show a new role of ANKZF1 in eliminating the stress-damaged mitochondria, reiterating the mito-protective role of Vms1/ANKZF1 during mitochondrial stresses. PINK1/Parkin signaling leads to polyubiquitination of outer mitochondrial membrane (OMM) proteins on stressed mitochondria. ANKZF1 functions as an adaptor protein, binding to polyubiquitinated OMM proteins via UBA domain and autophagosome receptor LC3 via LIR motif.
    DOI:  https://doi.org/10.1038/s41420-025-02638-y
  5. Mol Biol Cell. 2025 Jul 30. mbcE25060271
    Rab14 promotes Parkin mediated mitophagy.
    Samina Momtaz, Marco Padilla-Rodriguez, Paola Cruz Flores, Natalia Rulli, Nam Yong Lee, Jean M Wilson.
      Mitochondrial degradation by mitophagy is essential to maintain cell metabolism; dysregulation can result in the accumulation of damaged mitochondria. While the Rab family of small GTPase proteins are involved with vesicular trafficking in the endocytic and biosynthetic pathways, Rab-GTPases also have a role in mitochondrial integrity. However, a role for Rab14, a trans-Golgi network (TGN)-endosomal Rab-GTPase in mitophagy has not been described. In cells knocked down for Rab14, mitochondria acquire an elongated morphology and increased levels of mitochondrial proteins, whereas overexpression of Rab14 decreased these proteins. Furthermore, mito-Keima assays show increased mitophagy upon Rab14 overexpression. Rab14-induced mitophagy is dependent on Parkin expression, as well as TBK1 and PI3K activity, placing it in the Parkin-dependent mitophagy pathway. 3D-reconstruction shows contact site formation between Rab14 and mitochondria, and inhibition of the TGN kinase PI(4)KIIIβ decreases Rab14-mitochondria contact sites and prevents Rab14-mediated mitophagy, suggesting that TGN-derived Rab14 vesicles mediate mitophagy. These results suggest that Rab14 promotes mitophagy and plays an essential role in modulating cellular metabolism. [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-06-0271
  6. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2511890122
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like lipid transporter densities connected to mitophagic phagophores. A subpopulation of ATP synthases relocalized from cristae to the inner boundary membrane. The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by subtomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation being enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    Keywords:  autophagy; cryo-ET; mitochondria; mitophagy; prohibitin
    DOI:  https://doi.org/10.1073/pnas.2511890122
  7. J Neurophysiol. 2025 Aug 01.
    CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation.
    Xiaoke Qiu, Shaoda Lai, Yingyi Zhang, Shengtao Huang, Han Li, Junsheng Liu, Yong Huang, Zhinan Zhang.
      The chronic unpredictable mild stress (CUMS) paradigm influences the neuronal count in the dentate gyrus (DG) region of the hippocampus, potentially linking to mitophagy induced by mitochondrial fragmentation. Fission mitochondrial 1 (FIS1)/mitochondrial fission factor (MFF) represents one of the mechanisms regulating mitochondrial fission and autophagy. Herein, we investigated the effects of CUMS on mitophagy and mitochondrial fragmentation in hippocampal DG neurons, along with their modulation of the mitochondrial fission pathway governed by FIS1/MFF. Our results demonstrated that CUMS stress augmented mitophagy in hippocampal DG neurons. Concurrently, it exacerbated the tendency towards mitochondrial fragmentation. The impact on the upstream regulatory pathway of mitochondrial fragmentation manifested as upregulation of FIS1 and downregulation of MFF, resulting in a net loss of mitochondrial content and a subsequent energy deficit. These findings suggest that CUMS stress, by modulating the FIS1/MFF balance, increase mitophagy stemming from mitochondrial fragmentation in hippocampal DG neurons.
    Keywords:  Depression; FIS1; MFF; mitochondria fragmentation; mitophagy
    DOI:  https://doi.org/10.1152/jn.00523.2024
  8. Nat Commun. 2025 Jul 30. 16(1): 6996
    DHRS13 suppresses differentiation and mitophagy in glioma via retinoic acid and mitochondrial reactive oxygen species.
    Sunyoung Seo, Min Ji Park, Min Gi Park, Minseo Gwak, Yoonji Kim, Junseok Jang, Nayoung Hong, Bok-Sim Lee, Chohee Kim, Seonguk Jo, Hyun Bo Shim, Hyun-Jin Kim, Myung Hun Kim, Seo Hyun Yoo, Seunghyun Yoon, Sua Kim, Jae Hyuk Lee, Sang-Hun Choi, Seon Yong Lee, Gyu-Bum Yeon, Sung-Hye Park, Sung-Hak Kim, Hyunjeong Lee, Joo-Yong Lee, Dae-Sung Kim, Byung Cheon Lee, Jong-Whi Park, Hyunggee Kim.
      To elucidate the complex interplay of undifferentiated cancer cells in malignancy, we focus on the crucial mechanisms that maintain the undifferentiated state of cancer stem-like cells, which drive tumor growth and therapy resistance. Here, we identify a protein called dehydrogenase/reductase 13 (DHRS13) that is abundant in undifferentiated glioblastoma cells. DHRS13 is primarily located in the mitochondria and functions as a retinaldehyde reductase, converting all-trans-retinaldehyde to all-trans-retinol with high affinity for NADPH. Mechanistically, DHRS13 prevents glioma stem-like cells from differentiating by blocking retinoic acid signaling, thereby maintaining their undifferentiated state. Remarkably, the depletion of DHRS13 results in mitochondrial reactive oxygen species-driven mitophagy and cell death. Consequently, loss of DHRS13 leads to a significant decrease in tumor initiation and progression. These findings hold promise for the development of strategies that target undifferentiated cancer cells, potentially leading to improved treatment outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-62148-4
  9. Mitochondrion. 2025 Jul 28. pii: S1567-7249(25)00072-8. [Epub ahead of print] 102075
    Role of Prohibitins as Guardians of mitochondrial homeostasis.
    Sabrina Champsi, David A Hood.
      Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.
    Keywords:  Aging; Apoptosis; Mitochondria; Mitophagy; Prohibitin
    DOI:  https://doi.org/10.1016/j.mito.2025.102075
  10. Life Sci. 2025 Jul 30. pii: S0024-3205(25)00525-9. [Epub ahead of print] 123890
    Role of impaired mitochondrial dynamics and mitophagy in cardiovascular diseases: Possible therapeutic approaches.
    Sarmistha Sarkar, Aindrila Chattopadhyay, Debasish Bandyopadhyay.
      High mortality rates due to cardiovascular diseases (CVDs) fascinate the scientists worldwide in the past few decades to discover potent therapeutic strategies to save the victims. The myocardium being a highly active tissue, mitochondrial homeostasis and mitochondrial quality control system are crucial for maintaining optimal cardiac performance. Mitochondrial quality control mechanism is a finely tuned regulatory network encompassing mitochondrial biogenesis, mitochondrial dynamics and mitophagy and is an integral component of the mitochondrial response to stressor stimuli. Mitochondrial dynamics including the fusion and fission of mitochondrial membranes is regulated by an extensively conserved mechanism comprising a group of mitochondrial membrane proteins belonging to the dynamin family of GTPases. Emerging evidences indicate that defects in mitochondrial fusion or fission are intrinsically correlated with the pathophysiology of CVDs. Mitophagy is a kind of selective autophagy which removes damaged or redundant mitochondria. Experimental findings demonstrated that impairment of mitophagy in cardiomyocytes induces the accumulation of dysfunctional mitochondria, leading to the disruption of cellular homeostasis and consequently precipitating various CVDs. These findings speculate that pharmacological modulation of mitochondrial homeostasis including mitochondrial dynamics and mitophagy may represent a potential therapeutic approach in restoring cardiac physiology. This review summarizes the prevailing insight into the impact of disturbed mitochondrial dynamics and mitophagy in the pathogenesis of CVDs and also delineates the therapeutic potential of several relevant regulatory drugs that target mitochondrial function and quality control in alleviating mitochondrial impairment-related cardiac dysfunction.
    Keywords:  Cardiomyocytes; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.lfs.2025.123890
  11. Biomedicines. 2025 Jun 25. pii: 1553. [Epub ahead of print]13(7):
    Urolithin A in Central Nervous System Disorders: Therapeutic Applications and Challenges.
    Qiang Zhang, Wan Zhang, Xinya Yuan, Xiaohong Peng, Guangyuan Hu.
      With the global trend of population aging becoming increasingly pronounced, the incidence of central nervous system (CNS) disorders continues to rise, posing a significant challenge to public health systems worldwide. Currently, many CNS disorders lack effective treatments, prompting researchers to investigate the therapeutic potential of natural compounds. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins and ellagic acid, can cross the blood-brain barrier and exhibits a favorable safety profile. This review summarizes the biosynthesis, pharmacokinetic profile, and key biological effects of UA, including its promotion of mitophagy and mitochondrial homeostasis, as well as its anti-inflammatory, antioxidant, anti-senescence, and anti-apoptotic properties. We comprehensively summarize the preclinical evidence demonstrating UA's therapeutic potential in CNS disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Recent clinical trials involving UA are presented, followed by a thorough analysis of the challenges associated with translating UA-based interventions into clinical practice for CNS disorders. This work aims to support the development of UA-based therapies to improve patient outcomes and address the growing global burden of CNS disorders.
    Keywords:  central nervous system disorders; mitochondria; neuroprotection; urolithin A
    DOI:  https://doi.org/10.3390/biomedicines13071553
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