bims-tofagi Biomed News
on Mitophagy
Issue of 2025–03–16
six papers selected by
Michele Frison, University of Cambridge
  1. Structure of human PINK1 at a mitochondrial TOM-VDAC array.
  2. Quality control of mitochondrial nucleoids.
  3. A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy.
  4. The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
  5. The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins.
  6. The Intersection of Mitophagy and Autism Spectrum Disorder: A Systematic Review.
  1. Science. 2025 Mar 13. eadu6445
    Structure of human PINK1 at a mitochondrial TOM-VDAC array.
    Sylvie Callegari, Nicholas S Kirk, Zhong Yan Gan, Toby Dite, Simon A Cobbold, Andrew Leis, Laura F Dagley, Alisa Glukhova, David Komander.
      Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.
    DOI:  https://doi.org/10.1126/science.adu6445
  2. Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]
    Quality control of mitochondrial nucleoids.
    Hao Liu, Haixia Zhuang, Du Feng.
      Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.
    Keywords:  mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.005
  3. Cell Discov. 2025 Mar 11. 11(1): 22
    A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy.
    Mingzhu Tang, Dade Rong, Xiangzheng Gao, Guang Lu, Haimei Tang, Peng Wang, Ning-Yi Shao, Dajing Xia, Xin-Hua Feng, Wei-Feng He, Weilin Chen, Jia-Hong Lu, Wei Liu, Han-Ming Shen.
      PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41421-025-00774-4
  4. Autophagy. 2025 Mar 10.
    The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
    Jared T Field, Donald Chapman, Yan Hai, Saeid Ghavami, Adrian R West, Berkay Ozerklig, Ayesha Saleem, Julia Kline, Asher A Mendelson, Jason Kindrachuk, Barbara Triggs-Raine, Joseph W Gordon.
      Mitochondrial quality control is critical in muscle to ensure contractile and metabolic function. BNIP3L/Nix is a BCL2 member, a mitophagy receptor, and has been implicated in muscle atrophy. Human genome-wide association studies (GWAS) suggest altered BNIP3L expression could predispose to mitochondrial disease. To investigate BNIP3L function, we generated a muscle-specific knockout model. bnip3l knockout mice displayed a ragged-red fiber phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, bnip3l knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibers. Kinome and gene expression analyses revealed that bnip3l knockout impairs NFAT and MSTN (myostatin) signaling, with alterations in muscle fiber-type and evidence of regeneration. Mechanistic experiments demonstrated that BNIP3L modulates mitophagy, along with reticulophagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for BNIP3L coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.
    Keywords:  BNIP3L/Nix; calcium signaling; mitophagy; muscle; myostatin
    DOI:  https://doi.org/10.1080/15548627.2025.2476872
  5. J Biol Chem. 2025 Mar 12. pii: S0021-9258(25)00252-2. [Epub ahead of print] 108403
    The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins.
    Di Liu, Xin-Yu Huo, Xiaoli Zhang, Zai-Rong Zhang.
      Pathological stress can lead to failure in the translocation of mitochondrial proteins, resulting in accumulation of unimported proteins within the cytosol and upregulation of proteasome for their quality control. Malfunction or delay in protein clearance causes dysregulation of mitochondrial protein homeostasis, cellular toxicity, and diseases. Ubiquilins (UBQLNs) are known to serve as chaperone which associates with unimported mitochondrial membrane protein precursors, and facilitates their proteasomal degradation. However, how UBQLN-engaged proteins are ubiquitinated and efficiently targeted to the proteasome are poorly understood. Here, using mitochondrial membrane protein ATP5G1 as a model substrate, we report that E3 ubiquitin ligase RNF126 interacts with substrate-engaged UBQLN1, thereby promoting ubiquitination and degradation of unimported proteins during mitochondrial stress. We find that UBQLN1's ubiquitin-associated domain (UBA) recruits RNF126 when its middle domain binds to unimported protein substrate. Recombinant RNF126 forms ternary complex with UBQLN1 and pATP5G1 in vitro and catalyzes ubiquitination of UBQLN1-bound ATP5G1. Without RNF126, proteasomal degradation of ATP5G1 was compromised. These results explain how RNF126 and ubiquilins interplay to ensure specific quality control of unimported mitochondrial membrane proteins under pathophysiological conditions.
    Keywords:  ATP synthase F(0) complex subunit C1; RNF126; Ubiquilin; cytosolic quality control; mitochondrial membrane protein degradation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108403
  6. Int J Mol Sci. 2025 Feb 28. pii: 2217. [Epub ahead of print]26(5):
    The Intersection of Mitophagy and Autism Spectrum Disorder: A Systematic Review.
    Eleonora Kovacheva, Maria Gevezova, Nikolay Mehterov, Maria Kazakova, Victoria Sarafian.
      Autism spectrum disorder (ASD) is a group of neurodevelopmental and biobehavioral conditions that arises from complex interactions between environmental factors and physiological development in genetically predisposed individuals. Among the most frequently observed metabolic abnormalities in ASD is mitochondrial dysfunction. Mitochondria respond to cellular stress by altering their dynamics or initiating mitophagy. In neurons, the buildup of dysfunctional mitochondria and reactive oxygen species (ROS) poses a significant risk, as these cells cannot regenerate through division. To safeguard mitochondrial health, cells rely on an efficient "clean-up mechanism" to remove compromised organelles. Mitophagy, a specific form of autophagy, is responsible for regulating the turnover of flawed and non-functional mitochondria. Impairments in this process result in the accumulation of defective mitochondria in neurons, a characteristic of several neurodegenerative disorders associated with behavioral abnormalities. This systematic review offers an in-depth summary of the present knowledge of mitophagy and underscores its pivotal role in the pathogenesis of ASD.
    Keywords:  autism; mitophagy; pathways
    DOI:  https://doi.org/10.3390/ijms26052217
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