bims-tofagi Biomed News
on Mitophagy
Issue of 2026–09–20
nine papers selected by
Michele Frison, University of Cambridge
  1. Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
  2. Species-dependent activities of the PINK1-parkin axis.
  3. Multilayered interplay between the cGAS-STING pathway and autophagy.
  4. Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
  5. Ubiquitin receptor-mediated, ubiquitin-independent targeted protein degradation via 26S proteasomes.
  6. Quality control of glycogen through direct ubiquitylation by RNF213.
  7. Mitochondrial fission factor senses and governs ferroptosis.
  8. DFCP1-containing ER microdomains mediate lysosomal membrane repair.
  9. VCP at the crossroads of UPS and autophagy in cancer.
  1. Autophagy. 2026 Sep 16.
    Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
    Jiamin Yi, Xin Yong, Da Jia.
      Mitochondrial ubiquitination is a central component of mitochondrial quality control. The PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway established how loss of mitochondrial membrane potential can trigger a phospho-ubiquitin feed-forward cascade on the outer mitochondrial membrane (OMM). It remains less clear how mitochondrial ubiquitination is achieved when PRKN is absent or inactivated. In our recent work, we identify a recruitment platform organized by AMBRA1 (autophagy and beclin 1 regulator 1), in which RMC1 (regulator of MON1-CCZ1) positions HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) at mitochondria. This spatial arrangement promotes HUWE1-dependent ubiquitination and turnover of OMM proteins, including MFN2 (mitofusin 2), VDAC1 (voltage-dependent anion channel 1), and VDAC2 (voltage-dependent anion channel 2). Our findings raise the question of how cells select among distinct mitochondrial ubiquitination pathways and whether these pathways function independently, sequentially, or cooperatively.
    Keywords:  AMBRA1; HUWE1; PINK1-PRKN; RMC1; mitochondrial quality control; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2026.2735210
  2. Transl Neurodegener. 2026 Sep 18. pii: 48. [Epub ahead of print]15(1):
    Species-dependent activities of the PINK1-parkin axis.
    Wei Huang, Kecheng Chen, Jiayi Wen, Tong Zhang, Shihua Li, Xiao-Jiang Li, Weili Yang.
      In vitro studies have established that PTEN-induced putative kinase 1 (PINK1) and parkin are central regulators of mitophagy, and loss-of-function mutations in either gene can cause early-onset Parkinson's disease (PD). Although various animal models, including mice and pigs with PINK1 or PRKN knockout, have largely failed to recapitulate the neurodegeneration seen in PD patients, effective knockdown of PINK1 or PRKN in non-human primates, when achieving substantial protein depletion, does induce dopaminergic neuron loss in the substantia nigra and α‑synuclein pathology, suggesting that both the degree of protein loss and the species-dependent PINK1-parkin axis activity contribute to PD pathogenesis. This review compares pathological and behavioral outcomes of PINK1- and parkin-deficient animal models across species, illustrates diverse functions of the PINK1-parkin axis beyond mitophagy, discusses mechanisms underlying the species-dependent differences, and highlights the therapeutic potential of targeting this pathway. The review also underscores the necessity of considering species-specific mechanisms when investigating the PINK1/parkin pathway.
    Keywords:  Animal models; Non-human primate; PINK1; Parkinson’s disease; Species specificity; parkin
    DOI:  https://doi.org/10.1186/s40035-026-00586-w
  3. Autophagy Rep. 2026 ;5(1): 2728537
    Multilayered interplay between the cGAS-STING pathway and autophagy.
    Ze-Bo Huang, Xiang-Zheng Gao, Jin-Yi Lin, Du Feng, Guang Lu.
      The cGAS-STING pathway detects cytosolic dsDNA to initiate innate immune responses, serving as a critical surveillance system against infection and cellular stress. Autophagy is an evolutionarily conserved catabolic process that maintains homeostasis by degrading cytoplasmic components. Although these two systems operate through distinct mechanisms, recent studies have uncovered a complex bidirectional regulatory network that intimately links them. On the one hand, STING has an evolutionarily conserved capacity to induce TBK1-independent noncanonical autophagy, and recent studies further link this activity to TFEB-dependent lysosome biogenesis, expanding its functional repertoire beyond classical interferon induction. On the other hand, autophagy restricts cGAS-STING signaling by clearing cytosolic DNA and selectively degrading pathway components, thereby preventing excessive inflammation. Furthermore, mitophagy curtails the release of mitochondrial DNA, a potent cGAS agonist, and recent studies further implicate lysosomes as active signaling platforms associated with mtDNA release, LRRK2 activation, and STING-dependent NF-κB responses. In this review, we discuss recent advances in understanding how the cGAS-STING pathway and autophagy mutually regulate each other at the cellular level, focusing on the molecular mechanisms of this interplay, both canonical and noncanonical, and highlighting how their crosstalk shapes cellular homeostasis and stress adaptation.
    Keywords:  cGAS-STING pathway; innate immunity; lysosome; mitophagy; mtDNA; non-canonical autophagy
    DOI:  https://doi.org/10.1080/27694127.2026.2728537
  4. Aging Cell. 2026 Sep;25(9): e70718
    Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging.
    Renin Chang, Andy P Tsai, Boyang Wang, Kuan-Hao Tsui, Cheng-Yoong Pang, Chia-Jung Li.
      The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue-specific molecular clock of aging. We trace foundational single-cell and multi-tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single-cell and population-scale studies that have transformed the field: deep multi-tissue surveys revealing tissue-specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ-specific disease, and a two-step mechanism in which cryptic replication-error mutations become detectable through age-related clonal mosaicism. We discuss technologies such as single-cell mtDNA genotyping, duplex and long-read sequencing, and droplet digital PCR that now read the clock at single-molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA-driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood-based biomarker of biological age.
    Keywords:  aging; clonal expansion; heteroplasmy; mitochondrial DNA; molecular clock; respiratory chain deficiency; somatic mutation
    DOI:  https://doi.org/10.1111/acel.70718
  5. Sci Adv. 2026 Sep 18. 12(38): eaeh0227
    Ubiquitin receptor-mediated, ubiquitin-independent targeted protein degradation via 26S proteasomes.
    Seh Hoon Park, Yejin Jang, Soo-Yeon Lee, Eunseo Kim, Dawon Jeong, Insuk Byun, Jiseong Kim, Jisoo Yang, Chang-Han Lee, Dohyun Han, Jae-Hwan Nam, Min Jae Lee.
      The 26S proteasome engages with ubiquitinated substrates primarily through its constituent ubiquitin (Ub) receptors, which initiates a cascade of proteolytic processes. Leveraging this recognition mechanism, we developed a targeted protein degradation (TPD) strategy that recruits substrates directly to the proteasome, thereby bypassing the ubiquitination step. Our proteasome-targeting chimera, Protea-Tac, is a heterobifunctional protein degrader composed of a Ub receptor and an intracellular antibody. This chimera integrates into 26S proteasomes without altering their structural or functional integrity. Protea-Tac with cognate antibodies degraded various target proteins, including c-Fos, BRD4, FlagTDP43, HAtau, and GFPODC. We mechanistically demonstrated that this platform is (i) modular, allowing facile target switching, (ii) Ub independent, and (iii) highly target specific. Furthermore, Protea-Tac exhibited potent in vivo antitumor efficacy, posttranslationally inducing c-Fos degradation and substantially delaying tumor progression through both viral and nonviral delivery systems. These findings identify Protea-Tac as a distinct TPD platform capable of directly degrading intracellular proteins via engineered 26S proteasomes.
    DOI:  https://doi.org/10.1126/sciadv.aeh0227
  6. Nature. 2026 Sep 15.
    Quality control of glycogen through direct ubiquitylation by RNF213.
    Matthew C J Yip, Katerina Naydenova, Elsje G Otten, Alexander Heatley, Agnes Moe, Leonie Anton, Lucía de Los Reyes-Ramírez, Helen E Jolin, Frederic Langevin, Michal Wiacek, Catarina Franco, Anne Bertolotti, Wanda Kukulski, Andrew N J McKenzie, Felix Randow.
      Quality control of biomolecules is vital for organismal health. While DNA repair and protein quality control are well understood, how cells monitor other important biomolecules such as glycogen remains ill-defined. The accumulation of aberrant, poorly branched glycogen into insoluble polyglucosan bodies causes severe disease1,2. Here, we discover autophagy of ubiquitylated aberrant glycogen as a previously unrecognized quality control mechanism safeguarding the brain from polyglucosan buildup. This mechanism depends on the E3 ubiquitin ligase RNF213. Mice lacking ligase activity in RNF213 accumulate polyglucosan in cerebellum, pons, and hippocampus. Using cells engineered to produce polyglucosan, we show that RNF213 selectively ubiquitylates abnormal glycogen. Cryo-EM analysis of RNF213 bound to glycogen-derived maltoheptaose revealed its CBM20 domain binds linear oligosaccharides. Disrupting carbohydrate binding results in gain of E3 ligase activity towards physiological glycogen, indicating the CBM20 domain limits RNF213 activity towards physiological glycogen. Epistasis analysis places RNF213 upstream of LUBAC, suggesting a hierarchical network of multiple E3 ligases surveying glycogen quality. Ubiquitylated polyglucosan recruits the autophagy receptors SQSTM1, TAX1BP1, and optineurin, thereby triggering uptake into autophagosomes. These findings identify RNF213 as a quality control factor preventing polyglucosan accumulation in astrocytes through direct ubiquitylation of polyglucosan, revealing an essential role for non-protein ubiquitylation in glycogen quality control.
    DOI:  https://doi.org/10.1038/s41586-026-11139-6
  7. Nature. 2026 Sep 16.
    Mitochondrial fission factor senses and governs ferroptosis.
    Songjun Dai, Xiaoyan Dai, Tingting Zhang, Yuanyuan Qi, Xinquan Yang, Pengfei Diao, Chaodong Ge, Wenxiang Huang, Jisheng Ran, Xueliang Yang, Peng Zhang, Keke Zheng, Ruijun Wang, Hong Qian, Kunxiao Zhang, Junbing Wu, Caiyun Fu, Qian Ba, Junxia Min, Fudi Wang, Qiang Zhang.
      Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation and is implicated in diverse pathological states1-4. Although mitochondria and other organelles are increasingly being recognized as important modulators of ferroptosis5-7, a unifying mechanism that couples organelle dynamics to ferroptotic execution has remained elusive. Here using quantitative phosphoproteomics, we identified mitochondrial fission factor (MFF) as a key ferroptosis-selective regulator. Mechanistically, the lipid mediator 17-HETE promotes phosphorylation of MFF at Ser155, which triggers the coordinated fragmentation and dysfunction of mitochondria and peroxisomes. This remodelling intensifies interorganelle crosstalk, amplifies oxidative stress and accelerates ferroptotic death. To monitor this phosphorylation event in living cells, we developed MFF-SPARK, a phase-separation-based biosensor, for real-time tracking of ferroptosis through MFF activation. Using MFF-SPARK, we identified PKCβ and DUSP22 as a coordinated kinase-phosphatase pair that governs MFF phosphorylation. We also discovered avermectin B1 as a pharmacological activator of the PKCβ-MFF axis, which can sensitize tumours to ferroptosis in vivo. Together, our findings establish MFF phosphorylation as a central regulatory node in ferroptosis-associated organelle remodelling and provide a conceptual framework and toolbox for monitoring and pharmacologically interrogating ferroptosis.
    DOI:  https://doi.org/10.1038/s41586-026-11020-6
  8. Nat Cell Biol. 2026 Sep 15.
    DFCP1-containing ER microdomains mediate lysosomal membrane repair.
    Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.
      Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.
    DOI:  https://doi.org/10.1038/s41556-026-02062-z
  9. Genes Dis. 2027 Jan;14(1): 102264
    VCP at the crossroads of UPS and autophagy in cancer.
    Charlie J Hitchman, Julia I Phillips, Hee-Won Park, Hua Lu.
      Proteostasis is maintained by the coordinated action of the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathways. Valosin-containing protein (VCP/p97), an AAA + unfoldase, sits at its intersection by extracting ubiquitinated clients and assembling cofactor-defined complexes that determine substrate fate. In cancer, VCP up-regulation and altered cofactor recruitment rewire these ubiquitin-dependent routing decisions. By recruiting E3 ligases and deubiquitinases that remodel K48- and K63-linked ubiquitin chains, VCP biases substrates toward Ufd1-Npl4-coupled proteasomal turnover or autophagy-linked clearance, enabling oncogene stabilization or tumor suppressor loss. These principles are reflected in cancer axes that modulate autophagy flux, invasion and metastasis, PI3K/AKT/mTOR signaling, and immune evasion. The tumor suppressor p53 illustrates this complexity with state-dependent outcomes: VCP promotes proteasomal turnover of wild-type p53 through the canonical Ufd1-Npl4 complex, whereas it can stabilize the R273H hotspot mutant in a chaperone/holdase-like manner, prolonging gain-of-function phenotypes. Opposing regulators further control VCP function: PLAC8 enhances VCP-Ufd1-Npl4 activity and is linked to wild-type p53 turnover, PI3K/AKT/mTOR activation, and context-dependent autophagy effects. In contrast, SVIP can outcompete other VCP cofactors and, via acylation-dependent membrane targeting, redirect VCP toward lysosome-associated functions with predominantly tumor-suppressive effects. Collectively, this framework motivates therapeutic strategies that modulate VCP-cofactor interactions to regulate substrate degradative fate. Approaches include disrupting the Ufd1-Npl4 axis, biasing VCP from UPS to autophagy, altering subcellular localization, and reprogramming VCP for targeted proteolysis, with implications for cancer, fibrosis, neurodegeneration, and multisystem proteinopathy.
    Keywords:  Autophagy; Cancer; Ubiquitin-proteasome system; VCP/p97; p53
    DOI:  https://doi.org/10.1016/j.gendis.2026.102264
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