bims-tofagi Biomed News
on Mitophagy
Issue of 2026–04–12
twelve papers selected by
Michele Frison, University of Cambridge
  1. The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
  2. Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.
  3. STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
  4. Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.
  5. Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
  6. A single-nucleus RNA-seq dataset of the colon in Pink1-deficient and wild-type mice.
  7. Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
  8. DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
  9. African swine fever virus pE199L, as a mitophagy receptor, suppresses antiviral innate immunity to promote viral replication.
  10. Curcumin ameliorates hepatic insulin resistance by activating PINK1/Parkin-mediated mitophagy.
  11. In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
  12. Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
  1. Nat Commun. 2026 Apr 09.
    The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-71630-6
  2. Life Sci. 2026 Apr 07. pii: S0024-3205(26)00190-6. [Epub ahead of print] 124381
    Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.
    Jingjing Wang, Pei Wen, Zhixin Sun, Fengting Gou, Qing Fan, Yuheng He, Deming Zhao, Lifeng Yang.
      Prion diseases are chronic, transmissible, and neurodegenerative disorders that affect both humans and other mammals. Mitophagy is essential for maintaining mitochondrial homeostasis and normal neuronal function. Our previous research show that the PINK1-Parkin-dependent mitophagy pathway is impaired in the PrP106-126 induced prion disease model, yet the underlying downstream mechanisms remain elusive. We report that impaired phosphorylation of ubiquitin at Ser65 diminishes OPTN recruitment to mitochondria, thereby influence mitochondrial translocation of TBK1 and ATG9A, consequently suppresses TBK1 autophosphorylation that depends on the OPTN-ATG9A interaction. As a result, reduction of OPTN phosphorylation dependent on TBK1 inhibits autophagosome formation and ultimately leads to defective mitophagy. Importantly, overexpression of OPTN rescued the mitophagy impairment induced by PrP106-126 and partially restoring mitochondrial morphology and function. Our findings identify OPTN as a critical node, proposing its therapeutic targeting as a strategy to counteract prion disease progression.
    Keywords:  Mitophagy; OPTN; Phosphorylation; Prion diseases; TBK1
    DOI:  https://doi.org/10.1016/j.lfs.2026.124381
  3. Autophagy. 2026 Apr 11.
    STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
    Jin-Yi Lin, Ze-Bo Huang, Evandro F Fang, Guang Lu.
      PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.
    Keywords:  Alzheimer disease; PINK1; PRKN; STUB1; VCP/p97; memory; mitochondrial homeostasis; mitophagy; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2026.2658848
  4. Autophagy. 2026 Apr 11. 1-15
    Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.
    Changjuan Shao, Sabina Bhatta, Meena Kumari, Fengqin Wu, Sandra L Siedlak, Sandy Torres, Fanpeng Zhao, Xiongwei Zhu, Wenzhang Wang.
      Mutations in C19orf12, an orphan gene with elusive function, cause mitochondrial membrane protein-associated neurodegeneration (MPAN). Despite the intriguing mitochondrial deficits, the mechanisms underlying the loss of function of C19orf12 in MPAN pathogenesis remain unclear. In this study, we aim to explore the functional impacts of C19orf12 mutations on mitophagy in MPAN models in vitro and in vivo. Our findings suggest that C19orf12 regulates the turnover of mitophagy receptor BNIP3 proteins through the lysosomal degradation pathway. Disruption of this process leads to the accumulation of oxidized BNIP3 proteins on mitochondria that are ineffective in initiating mitophagy. Mechanistically, C19orf12 participates in protein condensate formation by liquid-liquid phase separation to facilitate BNIP3 protein turnover on the mitochondrial membrane. Along with mitophagy deficits, a rodent MPAN model exhibits motor deficits and core pathological features of MPAN, including iron accumulation, axonal spheroids, and neuroinflammation. This study underscores the pivotal role of C19orf12 in regulating the quality control of BNIP3 protein to control mitophagy, highlighting the significance of impaired mitophagy in the pathogenesis of MPAN.Abbreviations:  ATP: adenosine triphosphate; BafA: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BTZ: bortezomib; C19orf12: chromosome 19 open reading frame 12; CFP: cyan fluorescent protein; CHX: cycloheximide; DNP: dinitrophenyl; FCCP: carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; FRAP: fluorescence recovery after photobleaching; GFP: green fluorescent protein; H&E stain: haematoxylin and eosin stain; LCD: low complexity domain; LC/MS: liquid chromatography-mass spectrometry; LLPS: liquid-liquid phase seperation; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mito-SRAI: mitochondrial signal-retaining autophagy indicator; MG132: cbz-leu-leu-leucinal; MMP: mitochondrial membrane potential; MPAN: mitochondrial membrane protein-associated neurodegeneration; NBIA: neurodegeneration with brain iron accumulation;PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; STX17: syntaxin 17; TFAM: transcription factor A, mitochondrial; TOLLES: TOLerance of lysosomal EnvironmentS; YPet: YFP for energy transfer.
    Keywords:  Iron accumulation; LLPS; NBIA; mitochondrial membrane; mitophagosome; protein degradation
    DOI:  https://doi.org/10.1080/15548627.2026.2655834
  5. Biochemistry. 2026 Apr 06.
    Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
    Ashwini Kumar, Emmanouil Zacharioudakis.
      Mitochondria are increasingly recognized as signaling organelles that coordinate cell-fate decisions during stress. Because outer mitochondrial membrane (OMM) proteins are exposed to the cytosol, they are prominent substrates for ubiquitination, a dynamic post-translational modification that encodes information through diverse chain architectures and linkage types. In this review, we examine how ubiquitination of OMM proteins functions as a molecular switch that integrates mitochondrial stress signals and engages three major, often antagonistic, stress-response mechanisms: mitophagy, cell death, and innate immune signaling. We highlight an emerging concept that a stress-responsive "ubiquitin code" is written on OMM substrates, in which pathway selection is coordinated by the identity of ubiquitinated OMM proteins together with the linkage type and branching of attached polyubiquitin chains. We provide an updated overview of the E3 ubiquitin ligases and deubiquitinases (DUBs) that write and erase this code and summarize ubiquitin linkage types reported on key OMM substrates across these pathways. For mitophagy, we cover both PARKIN-dependent and PARKIN-independent mechanisms mediated by other E3 ligases and counteracted by DUBs. For innate immunity, we discuss how ubiquitination of OMM proteins regulates the MDA5/RIG-I-MAVS axis and NF-κB signaling. For cell death, we describe how ubiquitination of anti- and pro-apoptotic BCL-2 family proteins can either lower or increase the threshold for the induction of apoptosis. We also highlight the newfound role of PARKIN to drive apoptosis through a BAX/BAK-independent mechanism. Finally, we discuss therapeutic opportunities to reprogram OMM ubiquitination by targeting E3 ligases or DUBs directly, or by using PROTAC- and DUBTAC-based strategies.
    Keywords:  E3 ubiquitin ligases; apoptosis; deubiquitinases; innate immune signaling; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1021/acs.biochem.6c00007
  6. Sci Data. 2026 Apr 06.
    A single-nucleus RNA-seq dataset of the colon in Pink1-deficient and wild-type mice.
    Muhammad Junaid, Soo Jung Park, Yiseul Bae, Eun Jeong Lee, Su Bin Lim.
      PTEN-induced kinase 1 (Pink1), a familial Parkinson's associated gene, is a key regulator of mitochondrial and cellular energy homeostasis. Mutations in Pink1 disrupt mitophagy and perturbations in gastrointestinal homeostasis. This suggests the possibility that Pink1 deficiency may influence neurodegenerative processes by altering gut-to-brain signaling mechanisms. To facilitate investigation of gut-specific consequences of Pink1 deficiency, we generated a single-nucleus RNA sequencing (snRNA-seq) dataset from gut tissue of wild-type (WT) and Pink1 knockout (KO) mice. We identified major cell populations such as goblet cells, immune cells, and colonocytes, and characterized their transcriptional profiles. For technical validation, we utilized a publicly available murine gut (snRNA-seq) dataset. We then applied anchor-based label transfer and confirmed cell-type assignments via random forest classification. This rigorously validated dataset provides a robust resource for exploring shifts in cell-type composition and transcriptional alterations associated with Pink1 loss.
    DOI:  https://doi.org/10.1038/s41597-026-07193-4
  7. Circ Res. 2026 Apr 10. 138(8): e326985
    Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
    Xi Fang, Åsa B Gustafsson.
      Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.
    Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
  8. J Cell Mol Med. 2026 Apr;30(7): e71132
    DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
    Chul Hong Park, Donghyuk Shin, Kwang Chul Chung.
      Parkinson's disease (PD) is characterised by progressive neurodegeneration and is marked by the formation of Lewy bodies, which are intracellular aggregates primarily composed of α-synuclein. Mitochondrial dysfunction and impaired protein degradation pathways are thought to play critical roles in PD progression, contributing to the loss of dopaminergic neurons in the substantia nigra. Phosphorylation of α-synuclein has been shown to promote its aggregation, underscoring its potential role in disease progression. Parkin, an E3 ubiquitin ligase, is widely regarded as a pleiotropic neuroprotective protein that modulates the mitochondrial quality control, as well as metabolic turnover and the accumulation of α-synuclein. Death-associated protein kinase 1 (DAPK1), which is involved in the regulation of apoptosis and autophagy, has recently emerged as an important factor in neurodegeneration. While DAPK1 has been implicated in Alzheimer's disease through its role in tau aggregation and amyloid-β production, our findings suggest that DAPK1 may also influence PD-related pathways by phosphorylating parkin at Ser136 and Ser198. This phosphorylation promotes the mitochondrial transport of parkin, enhancing interaction with mitochondria-localised E3 ubiquitin ligase MITOL and consequently leading to the degradation of parkin. Given the neuroprotective role of parkin, its reduction increases the vulnerability of neurons to 6-hydroxydopamine-induced toxicity, potentially contributing to decreased neuronal survival. Together, these findings suggest that DAPK1 functions as a previously unrecognised modulator of parkin and could potentially influence PD-related neurodegenerative processes. This pathway may provide a mechanistic link between mitochondrial dysfunction, α-synuclein pathology and neuronal cell death.
    Keywords:  6‐OHDA; DAPK1; MITOL; neuronal toxicity; parkin; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.1111/jcmm.71132
  9. Autophagy. 2026 Apr 11. 1-20
    African swine fever virus pE199L, as a mitophagy receptor, suppresses antiviral innate immunity to promote viral replication.
    Xiaoxuan Li, Binbin Ren, Danyang Zhang, Miao Dan, Dongying Liu, Ziwei Zhang, Jiakai Zhao, Yuchen Nan, Julian A Hiscox, James P Stewart, Zixiang Zhu, Qin Zhao, Yani Sun.
      The African swine fever virus (ASFV) employs sophisticated strategies to promote viral replication in the host; however, the underlying mechanisms remain incompletely understood. Here, we demonstrated that the ASFV encoded pE199L protein acts as a potential mitophagy receptor that disrupted innate immunity through structural mimicry. The pE199L protein localized to mitochondria via its C terminal hydrophobic domain (155-199 aa) and induced mitochondrial fission by promoting DNM1L/Drp1 phosphorylation. Importantly, pE199L contained three LC3-interacting regions (LIRs: W35-I38, F157-L160, F193-L196) that directed autophagic degradation of key immune adaptors. Specifically, pE199L mediated mitophagic clearance of TBK1 (the CGAS-STING1 pathway) and MAVS (the RLR-MAVS pathway), thereby inhibiting type I interferon production and enhancing viral replication. This dual degradation mechanism was confirmed through rescue experiments using autophagy inhibitors and functional assays with LIR mutants. We identifted pE199L as the first canonical mitophagy receptor encoded by ASFV, unveiling a novel immune evasion strategy and a potential target for antiviral vaccine development.Abbreviations: 3-MA: 3-methyladenine; aa: amino acid; ASFV: African swine fever virus; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM1L/Drp1: dynamin 1 like; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; hpi: hour post-infection; IFN: interferon; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MT-CO2/COXII: mitochondrially encoded cytochrome c oxidase II; PINK1: PTEN induced kinase 1; poly(dA:dT): poly(deoxyadenylic-thymidylic) acid; poly(I:C): polyinosinic-polycytidylic acid; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type.
    Keywords:  African swine fever virus; LC3; innate immunity; mitophagy; pE199L
    DOI:  https://doi.org/10.1080/15548627.2026.2654982
  10. Sci Rep. 2026 Apr 08.
    Curcumin ameliorates hepatic insulin resistance by activating PINK1/Parkin-mediated mitophagy.
    Zhanhong Guo, Huan Zhang, Yinghong Kong.
      
    Keywords:  Curcumin; HepG2 cells; Insulin resistance; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1038/s41598-026-47924-6
  11. Autophagy. 2026 Apr 08.
    In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
    Yufei Huang, Tianyu Zheng, Xiaofeng Sun, Ruoxi Wang, Shujun Cai.
      Selective mitochondrial clearance by autophagy (mitophagy) is essential for development and cellular homeostasis. However, how phagophores acquire sufficient membrane to engulf large mitochondria remains poorly understood. Here, we studied the in situ architecture of forming mitophagosomes in the developing Drosophila intestine by combining cryo-electron tomography (cryo-ET), serialized on-grid lift-in sectioning for tomography (SOLIST), cryo-focused ion beam (cryo-FIB) milling, and volume electron microscopy. Our data reveal that the endoplasmic reticulum (ER) forms continuous membrane connections with the phagophore during mitophagosome formation. In Vps13D mutant enterocytes, stalled mitochondrial phagophore membrane expansion is associated with an accumulation of persistent ER-phagophore membrane continuities. Together, our findings support a model in which the ER can establish direct membrane continuity with the phagophore to facilitate rapid mitophagosome formation. AbbreviationAPF: after puparium formation; BLTP: bridge-like lipid transfer protein; CCS: cleaning cross-section; cryo-ET: cryo-electron tomography; cryo-FIB: cryo-focused ion beam; CTF: contrast transfer function; ER: endoplasmic reticulum; HPF: high-pressure freezing; mitolysosome: autolysosome containing a mitochondrion; mitophagophore: mitochondrial phagophore; mitophagy: selective mitochondrial clearance by autophagy; NGS: normal goat serum; OMM: outer mitochondrial membrane; OsO4: osmium tetroxide; PB: phosphate buffer; PBSTx: PBS containing 0.3% (w:t) Triton X-100; RCS: regular cross-section; RT: room temperature; RT-FIB-SEM: room-temperature focused ion beam scanning electron microscopy; SOLIST: serialized on-grid lift-in sectioning for tomography; TLD: Through-the-Lens Detector.
    Keywords:  Cryo-ET; Cryo-FIB; Drosophila; Vps13D; mitochondria; mitophagy; serial cryo-lift-out
    DOI:  https://doi.org/10.1080/15548627.2026.2657543
  12. Chem Commun (Camb). 2026 Apr 07.
    Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
    Zixuan Zhao, Hongling Li, Lijun Li, Jinping Liu, Qi Ai, Xin Wen, Baoxiang Gao.
      Mitochondrial autophagy (mitophagy) is pivotal for mitochondrial quality control and intracellular homeostasis. However, real-time visualization of mitochondrial inner membrane viscosity - a key biophysical parameter of mitophagy - remains challenging. To address this, a silicon rhodamine (SiR)-based dual-modal imaging probe was developed, enabling reliable real-time monitoring of mitophagic processes and providing novel insights into mitochondrial remodeling during autophagy.
    DOI:  https://doi.org/10.1039/d6cc00586a
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