bims-tofagi 2026-10-04 papers

Issue of 2026–10–04
seven papers selected by
Michele Frison, University of Cambridge

EMBO Rep. 2026 Sep 28.

PTEN-L inhibits mitophagy and GSDME-dependent pyroptosis via Parkin dephosphorylation.

Mitochondrial dysfunction is a potent trigger of inflammatory cell death; however, the precise signaling pathways linking mitochondrial damage to pyroptosis remain incompletely understood. Here, we identify a previously unrecognized pathway in which mitochondrial depolarization activates the PINK1-Parkin axis to drive GSDME-mediated pyroptosis, a process negatively regulated by the phosphatase PTEN-L. Upon activation, Parkin promotes the ubiquitination and proteasomal degradation of MCL-1, facilitating mitochondrial translocation and activation of BAX. This triggers cytochrome c release, caspase-3 activation, and subsequent cleavage and plasma membrane targeting of GSDME, ultimately leading to pyroptotic cell death. Conversely, PTEN-L functions as a master negative regulator that counteracts Parkin through dephosphorylation and inactivation of Parkin. This action not only suppresses mitophagy but also stabilizes MCL-1, thereby inhibiting the downstream BAX/BAK-caspase-3-GSDME cascade and subsequent pyroptosis. Thus, our findings reveal a phosphorylation-dependent regulatory switch centered on Parkin that functionally couples mitophagy regulation to GSDME-dependent pyroptosis, delineating a novel mitochondrial signaling pathway that integrates organelle quality control with cellular fate decisions under stress conditions.

DOI: https://doi.org/10.1038/s44319-026-00957-4

Autophagy. 2026 Sep 28. 1-24

Lactylation-mediated activation of HSPA5 upregulates VGLL3 expression to inhibit mitophagy-dependent ferroptosis following intracerebral hemorrhage.

Zhang QiXiang, Tang QiKai, Wang BaoFeng, Liu YiKui, Ma YuXiao, Xu AoQian, Xue YuXiao, YuHao Sun, LiuGuan Bian.

Intracerebral hemorrhage (ICH) is a devastating neurological disorder characterized by extensive neuronal death, in which ferroptosis has emerged as a central pathological mechanism. Yet, the role of mitophagy in regulating ferroptosis during ICH remains elusive. Herein, we identified a lactylation-mediated HSPA5 (heat shock protein family A (Hsp70) member 5)-VGLL3 (vestigial like family member 3) signaling axis that confers neuroprotection following ICH. We observed a marked upregulation of VGLL3 expression in ICH models, and loss-of-function experiments revealed that VGLL3 silencing exacerbated BNIP3 (BCL2/adenovirus E1B interacting protein 3)-BNIP3L/NIX (BCL2/adenovirus E1B interacting protein 3-like)-mediated, mitophagy-dependent ferroptosis. Mechanistically, VGLL3 enhanced EGLN3 (egl-9 family hypoxia-inducible factor 3) expression and reduced HIF1A/HIF-1α (hypoxia inducible factor 1, alpha subunit) stability, thereby suppressing BNIP3-BNIP3L-driven mitophagy. Upstream, HSPA5 activated VGLL3, and HSPA5 knockdown phenocopied the effects of VGLL3 silencing. Pharmacological activation of HSPA5 with the selective agonist BIP inducer X (BIX) suppressed mitophagy-dependent ferroptosis in cultured neurons, while in vivo BIX administration alleviated neuronal death and improved motor function in ICH mice. Epigenetic analyses further demonstrated that HSPA5 expression was transcriptionally modulated by histone H3-Lys18 (H3K18) lactylation, while its non-histone lactylation was catalyzed by the acetyltransferase EP300 (E1A binding protein p300) and removed by the NAD-dependent protein deacetylase SIRT1 (sirtuin 1). Collectively, our findings delineate a lactylation-driven HSPA5-VGLL3-EGLN3-HIF1A/HIF1-1α axis that represses BNIP3-BNIP3L-mediated, mitophagy-dependent ferroptosis. Targeting this pathway may provide a mechanistic rationale and therapeutic strategy for mitigating neuronal injury and functional deficits following ICH.Abbreviations: BNIP3: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; EGLN3: egl-9 family hypoxia-inducible factor 3; GPX4: glutathione peroxidase 4; GSH: glutathione; GSSG: oxidized glutathione; HIF1A/HIF-1α: hypoxia inducible factor 1, alpha subunit; HSPA5: heat shock protein family A (Hsp70) member 5; IB: immunoblot; ICH: intracerebral hemorrhage; MDA: malondialdehyde; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; VGLL3: vestigial like family member 3.

Keywords: Ferroptosis; HSPA5; ICH; VGLL3; mitophagy

DOI: https://doi.org/10.1080/15548627.2026.2726746

Cell. 2026 Oct 01. pii: S0092-8674(26)01072-X. [Epub ahead of print]189(20): 6214-6216

Mitochondria before we knew them.

Courtney W Stairs, Ryan M R Gawryluk.

In this issue of Cell, Chen et al. chart mitochondrial proteome diversity across eukaryotes, revealing an unexpectedly complex ancestral proteome alongside extensive lineage-specific innovation. Their broad phylogenetic reconstruction provides new insights into the mitochondrial proteome of the last eukaryotic common ancestor while unearthing a wealth of unexplored mitochondrial biology outside of traditional model systems.

DOI: https://doi.org/10.1016/j.cell.2026.09.003

Mol Cell. 2026 Oct 01. pii: S1097-2765(26)00621-0. [Epub ahead of print]86(19): 3897-3914.e18

Ubiquitin chain editing promotes p97/VCP-dependent removal of RPA from DNA.

Matthew Drake, Xianzhen Zhou, Alexandra McStea, Benjamin Foster, Kay Yi Chong, Martin Attwood, Leslye Roca Burgos, Laura Bennett, Sneha Anand, Merve Kaplan, Jessica J Lu, Vaishnavi Ravikumar, Marjorie Fournier, Elena Navarro-Guerrero, Michael Ranes, Weston B Struwe, Christopher Staples, Daniel Ebner, Ian Gibbs-Seymour.

DNA repair requires dynamic control of proteins on single-stranded DNA (ssDNA), yet how ubiquitin signaling regulates ssDNA-bound factors remains poorly understood. Here, we identify in human cells a ubiquitin chain-editing mechanism that promotes extraction of replication protein A (RPA) from ssDNA. We show that RPA stimulates the deubiquitinase ZUP1 and enhances its activity toward K63 linkages within ubiquitin chains. In response to DNA damage, RPA is modified with branched K48-K63 ubiquitin chains. ZUP1 selectively removes K63 linkages from these chains, remodeling the ubiquitin signal on RPA. We show that ZUP1-mediated editing of branched ubiquitin chains promotes p97/VCP-dependent removal of ubiquitinated RPA from ssDNA. Loss of ZUP1 causes accumulation of branched ubiquitin chains on RPA and pathological RPA trapping on ssDNA, resulting in elevated ssDNA signaling and genome instability. Together, our findings identify ubiquitin chain editing as a mechanism that controls RPA dynamics on ssDNA and enables p97/VCP-mediated protein extraction during DNA repair.

Keywords: DNA repair; DUBs; RFWD3; RPA; VCP; ZUP1; deubiquitinases; genome stability; p97; ssDNA; ubiquitin

DOI: https://doi.org/10.1016/j.molcel.2026.09.004

Nat Commun. 2026 Aug 26. pii: 10238. [Epub ahead of print]17(1):

A redox switch on CDC48 regulates peroxisomal function via controlling peroxisome-associated protein degradation.

Jialong Li, Yandong Wang, Ronghui Pan, Rongcheng Lin.

Peroxisomes are single-membrane-bound organelles essential for diverse metabolic reactions and cellular redox homeostasis, yet the contribution of ubiquitin-proteasome system to peroxisomal biology remains unclear. Here, we demonstrate that the AAA-ATPase complex comprising Cell Division Cycle48 (CDC48), Nuclear Protein Localization4 (NPL4) and Ubiquitin Fusion Degradation1 (UFD1) is indispensable for peroxisomal biogenesis and physiological function in Arabidopsis. We identify the peroxisomal membrane peroxin PEX22 as a direct substrate of the CDC48 complex and show that this complex promotes ubiquitin-dependent PEX22 turnover. Genetic analyses place CDC48 complex upstream of PEX22 in controlling peroxisomal biogenesis and activity. Moreover, H₂O₂‑triggered Cys271 oxidation represses CDC48 ATPase activity, stabilizing PEX22 via slowed degradation; nucleoredoxin NRX1 reduces oxidized CDC48 to recover its function. Consistently, transgenic plants harboring the redox-insensitive CDC48-C271S variant display accelerated PEX22 turnover and enhanced susceptibility to oxidative stress. Collectively, our findings establish the CDC48 complex as a putative H₂O₂ sensor that governs ubiquitin-mediated peroxisome-associated protein degradation (PexAD), enabling fine-tuning of peroxisomal performance in plant development and upon environmental stress.

DOI: https://doi.org/10.1038/s41467-026-77146-3

bioRxiv. 2026 Sep 27. pii: 2026.09.24.754271. [Epub ahead of print]

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age.

Sarah Jean Shemtov, Eric Hwang, Claire S Chung, Herbert Anson, Lucy Carrillo, Sangmin Lee, Ivetta Vorobyova, Junxiang Wan, Scott R Kennedy, Amy R Vandiver, Bert M Verheijen, Whitaker Cohn, Bérénice A Benayoun, Max A Thorwald, Pinchas Cohen, Jonathan Wanagat, Jean-François Gout, Marc Vermulst.

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

DOI: https://doi.org/10.64898/2026.09.24.754271

Nat Commun. 2026 08 31. pii: 10374. [Epub ahead of print]17(1):

A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.

Elisabeth Holzer, Justyna Sawa-Makarska, Daniel Bernklau, Julia Romanov, Martina Schuschnig, Sascha Martens.

Autophagy degrades cellular material by sequestering it within autophagosomes, which form de novo from precursors called phagophores. Phagophore assembly and expansion require ATG9A-positive seed compartments, the lipid transfer protein ATG2A, and the class III phosphatidylinositol 3-phosphate kinase complex I (PI3KC3-C1). PI3KC3-C1 synthesizes phosphatidylinositol 3-phosphate (PI3P), a key lipid that drives downstream processes for phagophore expansion, including ATG8 lipidation. We find that ATG9A compartments contain only traces of phosphatidylinositol (PI), likely insufficient for efficient PI3P production or recruitment of PI3P-binding effectors. Nevertheless, ATG2A is recruited to these compartments and mediates lipid transfer, including PI, into them. Remarkably, even without detectable PI3P, ATG9A compartments are direct substrates for ATG8 lipidation, and ATG8 proteins themselves enhance ATG2A-mediated lipid transfer. In cells, ATG2A is essential for the appearance of PI3P on ATG9A compartments. Our findings support a model in which a lipid transfer-driven feedback loop activates ATG9A compartments for phagophore expansion.

DOI: https://doi.org/10.1038/s41467-026-77368-5