bims-tofagi 2026-11-15 papers

bims-tofagi

Biomed News

on Mitophagy

Issue of 2026–11–15
eight papers selected by
Michele Frison, University of Cambridge

SUMO-2/3 modification of PINK1 restrains basal mitophagy through MAPL-dependent regulation of mitochondrial surveillance.
The integration of protein and organelle degradation systems and its pathophysiological functions.
MTCH2 acts as a novel inhibitory receptor to suppress germ cell mitophagy by tethering BECN1, thereby maintaining mitochondrial homeostasis and male fertility.
PINK1‑regulated mitophagy dysfunction in the pathogenesis of Parkinson's disease (Review).
TRIM13 (tripartite motif-containing 13) improves mitophagy of dendritic cells via promoting SESN2 (sestrin 2)-induced K63-linked ubiquitination in sepsis.
Serine-65 phosphorylated ubiquitin associates with soluble tau and seeding activity in Alzheimer's disease.
RUNX1-BNIP3-mediated mitophagy regulates hepatocyte ferroptosis by promoting SLC25A28 degradation.
Impaired Exercise-Induced Mitophagy in Aged Muscle Coincides With Altered mitoAMPKα in Male Mice.

J Biol Chem. 2026 Nov 13. pii: S0021-9258(26)02625-6. [Epub ahead of print] 113753

SUMO-2/3 modification of PINK1 restrains basal mitophagy through MAPL-dependent regulation of mitochondrial surveillance.

Nitheyaa Shree Ramesh, Richard Seager, Kevin A Wilkinson, Jeremy M Henley.

  The mitochondrial kinase PTEN-induced kinase 1 (PINK1) initiates mitophagy in response to mitochondrial damage, yet mechanisms that constrain its activation under basal conditions remain incompletely defined. Here, we identify a non-canonical SUMO 2/3 modification of PINK1 that suppresses basal mitophagy. We show that the mitochondrial E3 ligase mitochondrial-anchored protein ligase (MAPL/MUL1) promotes PINK1 SUMO-2/3 modification, while MAPL depletion reduces SUMOylation and enhances basal mitophagy. Targeted deSUMOylation augments mitophagy. These findings reveal a novel SUMO-based checkpoint for basal PINK1 activation and mitochondrial quality control.

Keywords:  MAPL; PINK1; SUMO-2/3; SUMOylation; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1016/j.jbc.2026.113753
Nat Rev Mol Cell Biol. 2026 Nov 09.

The integration of protein and organelle degradation systems and its pathophysiological functions.

Florian Wilfling, Ivan Dikic.

Timely removal of defective or superfluous cellular components, including misfolded proteins, aberrant protein complexes and damaged organelles, is essential for maintaining cellular homeostasis and adaptation to stress. This process is controlled by an intricate interplay between two principal degradation systems, the ubiquitin-proteasome system and autophagy, which together mediate the recognition, selection and elimination of diverse substrates. In this Review, we discuss how proteins and organelles are dynamically partitioned between these catabolic pathways in response to physiological demands, cellular stress and damage. We highlight the mechanisms of substrate sequestration, the spatial and temporal organization of the degradation machineries and the compensatory responses that preserve proteostasis when one pathway is compromised, including the coordination with the unfolded protein response. We also examine how selective pathways such as endoplasmic reticulum phagy and mitophagy remodel or eliminate damaged organelles. Recent advances in electron tomography have revealed the ultrastructural basis of these networks, providing insights into their architecture and dynamics. Finally, we discuss how defects in these degradation systems contribute to ageing, cancer, neurodegeneration and other pathologies.

DOI: https://doi.org/10.1038/s41580-026-01037-0
Cell Death Dis. 2026 Aug 18. pii: 963. [Epub ahead of print]17(1):

MTCH2 acts as a novel inhibitory receptor to suppress germ cell mitophagy by tethering BECN1, thereby maintaining mitochondrial homeostasis and male fertility.

Mengxing Cai, Ruifang Ren, Huiling Shu, Yanyan Yang, Longhai Dai, Yanming Dong, Xiazhou Fu, Yibin Cheng.

Mitochondria play a pivotal role in spermatogenesis and male fertility, in which the selective autophagic degradation of mitochondria (mitophagy) constitutes a key process. In this study, we identify mitochondrial carrier homolog 2 (MTCH2) as a novel and critical regulator of germ cell mitophagy. Localized to the mitochondrial outer membrane (OMM), MTCH2 directly interacts with the core autophagy protein BECN1, thereby inhibiting autophagic flux and specifically suppressing mitophagy. Germ cell-specific heterozygous deletion of Mtch2 was sufficient to cause profound spermatogenic defects, including disorganized seminiferous tubules, vacuolization, mitochondrial sheath abnormalities, and significantly impaired sperm fertilization capacity. Transcriptomic profiling revealed that MTCH2 deficiency dysregulates pathways central to mitochondrial function and programmed cell death. Importantly, augmenting autophagy ameliorated mitochondrial dysfunction induced by MTCH2 deficiency, as characterized by impaired mitochondrial membrane potential, elevated mitochondrial reactive oxygen species (mtROS) production and cellular ROS levels. Collectively, our findings establish MTCH2 as an essential negative regulator of mitophagy that partners with BECN1 to maintain mitochondrial homeostasis, thereby ensuring normal spermatogenesis and male fertility.

DOI: https://doi.org/10.1038/s41419-026-09165-3
Mol Med Rep. 2027 Jan;pii: 11. [Epub ahead of print]35(1):

PINK1‑regulated mitophagy dysfunction in the pathogenesis of Parkinson's disease (Review).

Han-Liang Dan, Shu-Er Liu, Yu-Jie Zhao, Zi-Fan Zhu, Hao-Gang Li, Yi-Xiang Huang, Mei Chen, Yi-Hui Zhang, Hui-Xin Ai, Xiao-Hui Huang, Hai-Yun Zhao, Zheng Liu, Pan Zou, Maslinda Musa.

  Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α‑synuclein forming Lewy bodies. Emerging evidence highlights mitochondrial dysfunction as an important and early event in PD pathogenesis. Among the key regulators of mitochondrial quality control, PTEN‑induced kinase 1 (PINK1) plays a pivotal role by initiating mitophagy, the selective clearance of damaged mitochondria. Under physiological conditions, PINK1 is rapidly degraded, whereas mitochondrial depolarization stabilizes PINK1 on the outer mitochondrial membrane, where it recruits and activates Parkin, an E3 ubiquitin ligase, to promote mitophagy. Loss‑of‑function mutations in PINK1 also disrupt this process, leading to the accumulation of dysfunctional mitochondria, oxidative stress, abnormal calcium homeostasis and neuronal apoptosis. Furthermore, PINK1 deficiency has been shown to exacerbate α‑synuclein aggregation, impair synaptic transmission and activate neuroinflammatory pathways, collectively accelerating dopaminergic neurodegeneration. Therapeutic strategies aimed at restoring or enhancing PINK1‑mediated mitophagy through pharmacological activation, gene delivery or modulation of parallel pathways‑represent a promising avenue for PD intervention. Continued elucidation of the molecular functions of PINK1 will provide critical insights into mitochondrial homeostasis and novel therapeutic targets for PD.

Keywords:  PINK1; Parkinson's disease; mitochondrial autophagy

DOI:  https://doi.org/10.3892/mmr.2026.14069
Autophagy. 2026 Nov 11. 1-21

TRIM13 (tripartite motif-containing 13) improves mitophagy of dendritic cells via promoting SESN2 (sestrin 2)-induced K63-linked ubiquitination in sepsis.

Bing Sun, Hua-Yong Chen, Lin-Wen Zheng, Si-Qin Yang, Zhao-Hong Chen, Yong-Ming Yao.

  Sepsis constitutes a life-threatening organ dysfunction caused by a dysregulated host response to infection. SESN2 (sestrin 2), an evolutionarily conserved stress-responsive protein, is a pivotal regulator of cellular homeostasis. Here, we identified TRIM13 (tripartite motif-containing 13) as a regulator that modulated the stability of SESN2 at the post-translational level. Specifically, TRIM13 promoted K63-linked ubiquitination of SESN2 with subsequent upregulation of its functional activation. Ubiquitinated SESN2 initiated a selective macroautophagic/autophagic program that facilitated the recruitment of SQSTM1/p62 (sequestosome 1/p62) to mitochondrial surfaces. The enhanced interaction between ubiquitinated SESN2 and the mitophagy receptor FUNDC1 (FUN14 domain-containing 1) at mitochondria-associated membranes (MAMs), facilitated by this modification, potentiated the mitophagic clearance of damaged mitochondria. In addition, it inhibited the interaction between FUNDC1 and RIPK3 (receptor-interacting serine-threonine kinase 3), which in turn ameliorated dysfunction and necroptosis of dendritic cells (DCs) upon sepsis. Thus, our findings establish that TRIM13 mitigates septic responses by activating SESN2-mediated mitophagy through ubiquitination, offering new insights into potential immunomodulatory strategies for sepsis.Abbreviations: AF: AlphaFold; BECN1: beclin 1, autophagy related; CLP: cecal ligation and puncture; co-IP: co-immunoprecipitation; DAMPs: danger/damageassociated molecular patterns; DCs: dendritic cells; DEGs: differentially expressed genes; FUNDC1: FUN14 domain containing 1; IL: interleukin; LPS: lipopolysaccharide; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MHC: major histocompatibility complex; MLKL: mixed lineage kinase domain-like; Nec-1: necrostatin-1; PBMCs: peripheral blood mononuclear cells; RIPK3: receptor-interacting serine-threonine kinase 3; SESN2: sestrin 2; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TLR: toll-like receptor; TNF: tumor necrosis factor; TRAF6: TNF receptor-associated factor 6; TRIM13: tripartite motif-containing 13; ULK1: unc-51 like kinase 1; UPR: unfolded protein response; UPS: ubiquitinproteasome system; WT: wild-type.

Keywords:  Immune dysfunction; mitophagy; sepsis; sestrin 2; tripartite motif-containing 13

DOI:  https://doi.org/10.1080/15548627.2026.2758017
Nat Commun. 2026 10 12. pii: 11565. [Epub ahead of print]17(1):

Serine-65 phosphorylated ubiquitin associates with soluble tau and seeding activity in Alzheimer's disease.

Tingxiang Yan, Xu Hou, Jens O Watzlawik, Dennis W Dickson, Fabienne C Fiesel, Wolfdieter Springer.

Tau propagation is a key driver of Alzheimer's disease (AD), yet selective markers of seeding-competent tau remain elusive. Ubiquitin phosphorylated at Serine-65 (pS65-Ub) is a PINK1-derived cellular stress signal that accumulates in AD with elevated tau pathology, but its relationship to tau seeding is unknown. Here, using postmortem brain tissue from female and male donors, we show that a subset of tau is covalently modified by pS65-Ub in AD brain. The pS65-Ub-associated tau population is elevated in AD and is enriched in soluble, high-molecular-weight, oligomeric, and hyperphosphorylated tau species. Across AD cases, soluble pS65-Ub-associated tau levels strongly correlate with tau seeding activity. Tau species isolated with pS65-Ub antibodies exhibit seeding activity, whereas removal of pS65-Ub-associated material markedly reduces seeding from AD brain extracts. Together, these findings identify pS65-Ub as a disease-enriched molecular feature of a seed-competent tau population and link cellular stress signaling with pathological tau propagation in AD.

DOI: https://doi.org/10.1038/s41467-026-78418-8
Redox Biol. 2026 Nov 04. pii: S2213-2317(26)00464-7. [Epub ahead of print]98 104465

RUNX1-BNIP3-mediated mitophagy regulates hepatocyte ferroptosis by promoting SLC25A28 degradation.

Zi-Yan Hu, Xue-Qi Wang, Yi-Feng Huang, Ming Lou, Ming-Shan Chen, Jia-Xin Wang, Fu-Wei Jiang, Zhuo-Yu Liu, Yue Cheng, Jing Zheng, Hong-Li Si, Jin-Long Li, Yi Zhao.

  Lambda-cyhalothrin (LCT), a commonly used pyrethroid insecticide, has been increasingly considered as a possible risk factor for liver injury. Ferroptosis, a form of regulated cell death resulting from the accumulation of iron and lipid peroxidation, is identified by mitochondrial dysfunction, but its mechanisms underlying LCT-induced liver damage remain poorly defined. Runt-related transcription factor 1 (RUNX1) is a transcription factor involved in diverse developmental and stress-responsive processes, yet its role and regulation in xenobiotic-induced liver injury remain unclear. Here, we investigated whether RUNX1-BNIP3-mediated mitophagy links mitochondrial iron homeostasis to ferroptosis-associated liver injury following LCT exposure. We showed that LCT exposure induced structural and functional liver injury accompanied by ferroptosis, impaired autophagic flux, and defective BNIP3-mediated mitophagy. Mechanistically, LCT suppressed RUNX1 expression, resulting in decreased BNIP3 transcription and consequently compromising mitophagic clearance of the mitochondrial iron importer SLC25A28. The resulting iron accumulation, glutathione imbalance and lipid peroxidation could contribute to ferroptosis and accelerate hepatocellular senescence. Of note, RUNX1 or BNIP3 overexpression efficiently restored mitophagy and promoted SLC25A28 turnover, thereby suppressing ferroptosis and cellular senescence. However, these benefits were abolished by BNIP3 knockdown or SLC25A28 overexpression. The results further identified SLC25A28 as an important downstream mediator of BNIP3-mediated mitophagy. Together, these findings identify that RUNX1 represents an important regulatory factor involved in LCT-induced liver injury by regulating BNIP3-dependent mitophagy and facilitating SLC25A28 turnover, thereby inhibiting ferroptosis and attenuating hepatocellular senescence. Our study uncovers that modulation of the hepatic RUNX1-BNIP3-SLC25A28 axis may represent a potential strategy for mitigating LCT-induced liver injury.

Keywords:  Ferroptosis; Lambda-cyhalothrin; Mitophagy; RUNX1; SLC25A28

DOI:  https://doi.org/10.1016/j.redox.2026.104465
Aging Cell. 2026 Nov;pii: e70827. [Epub ahead of print]25(11):

Impaired Exercise-Induced Mitophagy in Aged Muscle Coincides With Altered mitoAMPKα in Male Mice.

Niloufar Amiri, Anna S Nichenko, Alex Churchill, Orion S Willoughby, Torin D Pettit, Charles P Najt, Ricard A Rodriguez-Mias, Judit Villen, Joshua C Drake.

We demonstrate that the capacity for acute exercise to induce mitophagy in skeletal muscle is impaired in old male mice and corresponds to a loss of mitoAMPKα. We present evidence of age-dependent, exercise-induced phosphorylation of AMPK at S491, which may predispose mitoAMPKα to degradation by the E3-ubiquitin ligase Trim72. Our findings highlight the need to understand how aging alters spatial responses to energetic stressors, like exercise.

DOI: https://doi.org/10.1111/acel.70827