bims-tofagi 2026-10-25 papers

Issue of 2026–10–25
five papers selected by
Michele Frison, University of Cambridge

Autophagy. 2026 Oct 20.

PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.

Chenghao Yan, Xu Liu, Xinyu Gong, Xiaofang Wu, Haodong Xu, Liming Wang.

Mitochondrial damage is a potent trigger of inflammatory cell death; however, how damaged mitochondria transduce stress signals to initiate cell death execution, and how this process is finely regulated, remain incompletely understood. We recently identified that the PINK1-PRKN axis, activated upon mitochondrial depolarization, not only initiates mitophagy but also drives pyroptosis via the ubiquitination and degradation of MCL1, which in turn promotes BAX and BAK1 activation, leading to CASP3 activation and GSDME cleavage. PTEN-L functions as a negative regulator of this pathway by directly dephosphorylating PRKN, which concurrently suppresses both mitophagy and pyroptosis, thereby coupling organelle quality control to inflammatory cell death.

Keywords: GSDME-dependent pyroptosis; PINK1-PRKN axis; PTEN-L dephosphorylation; mitochondrial damage; mitophagy

DOI: https://doi.org/10.1080/15548627.2026.2751925

Nature. 2026 Oct 21.

GRP75-dependent SIMPA mediates inter-organellar quality control.

Mitochondria are bound by a double membrane and are semiautonomous organelles, rendering them highly vulnerable to global and internal proteostatic stress1. Multiple surveillance mechanisms at proteostatic and inter-organellar levels have evolved to maintain mitochondrial integrity and cellular health2-7. However, the precise mechanisms by which proteostatic damage relays stress signals across organelles and how the quality surveillance machinery coordinates these functions remain unknown. Here we report that under proteostatic stress, damaged mitochondrial proteins are sequestered to form stress-induced mitochondrial protein aggregates (SIMPAs) that activate specific quality control mechanisms in a spatially confined manner without perturbing the mitochondrial network. Quantitative proteomic and correlative light-electron microscopy analysis revealed that SIMPA mediates inter-organellar communication via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes. Mechanistically, GRP75 coordinates SIMPA biogenesis and focally activates endoplasmic reticulum unfolded protein response pathways via mitochondria-endoplasmic reticulum contact sites or mitochondrial-associated membranes for the targeted clearance of SIMPAs. Functionally, in both cellular and liver disease models, we found that a GRP75-dependent SIMPA signalling cascade attenuates mitochondrial stress and preserves mitochondrial integrity under proteotoxic stress. Overall, we show that SIMPAs, functioning as protein condensates, serve as a central cross-compartment communication hub for mitochondrial quality control, supporting cellular and organismal fitness.

DOI: https://doi.org/10.1038/s41586-026-10733-y

Science. 2026 Oct 22. 394(6822): eaea2181

BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.

Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.

The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.

DOI: https://doi.org/10.1126/science.aea2181

Cell Res. 2026 Oct 20.

Metabolic hallmarks of regulated cell death.

Rui Kang, Xin Chen, Guido Kroemer, Daolin Tang.

Regulated cell death (RCD) is characterized by distinct molecular execution mechanisms, but its initiation, progression, and biological consequences are increasingly recognized as being shaped by cellular metabolism. Bioenergetic state, redox homeostasis, nutrient availability, metal ion metabolism, inflammatory metabolism, and organelle function collectively determine cellular susceptibility to death and influence the activation and execution of diverse RCD programs. In this review, we synthesize the metabolic hallmarks of established, independently validated, and recently proposed forms of RCD, highlighting both their mechanistic diversity and their extensive metabolic convergence. We then examine the endogenous mechanisms that maintain metabolic homeostasis and discuss how their disruption reshapes cell death responses in human disease and therapeutic contexts. Together, these insights provide a guide to the metabolic landscape of RCD and reveal metabolism not only as a modifier of cell death, but as a fundamental determinant of when, how, and with what consequences cells die. We conclude by discussing key conceptual and mechanistic challenges and emerging opportunities for therapeutically exploiting the metabolic control of RCD.

DOI: https://doi.org/10.1038/s41422-026-01306-9

Autophagy. 2026 Oct 23.

SSH1 knockdown increases autophagosome formation through ATG9A recruitment and promotes tau protein degradation.

Morgan C Stephens, Richard I Han, Alma M Perez, Hilary Chester, Maria de Haro, Arsh Ali, Amy Hammett, Ruhee Dere, Ismael Al-Ramahi, Juan Botas.

Pathological accumulation of MAPT/tau protein is a defining feature of Alzheimer disease (AD) and related tauopathies, highlighting the need to identify druggable regulators of MAPT/tau clearance. Using Drosophila behavioral assays focused on cytoskeletal remodeling pathways dysregulated in AD, we identified genes whose genetic modulation mitigates MAPT/tau-induced behavioral deficits. These modifiers were validated by histopathology and mechanistically examined in human tauopathy cell models to determine their impact on autophagy-dependent MAPT/tau degradation. Autophagic flux, ATG9A trafficking, and autophagosome biogenesis were further analyzed. Across models, reduction of the phosphatase SSH1 consistently lowered steady-state MAPT/tau levels by enhancing autophagic flux through a mechanism distinct from its canonical regulation of CFL1. Mechanistically, SSH1 functions as a negative regulator of early autophagosome formation: SSH1 depletion promotes ATG9A mobilization to the endoplasmic reticulum-phagophore assembly site (ER-PAS), thereby accelerating autophagic vesicle biogenesis. Importantly, the MAPT/tau-lowering effect of Dmssh attenuation was abolished in flies haploinsufficient for DmAtg9, demonstrating that SSH1-mediated MAPT/tau clearance requires ATG9 function. Consistent with a direct regulatory interaction, in vitro phosphatase assays revealed that recombinant SSH1 decreases ATG9A phosphorylation in the presence of actin, identifying an SSH1-ATG9A regulatory axis controlling autophagosome initiation. These findings position SSH1 as a nodal inhibitor of autophagy initiation whose inhibition enhances MAPT/tau proteolysis. Notably, SSH1 haploinsufficiency also reduces SNCA/α-synuclein accumulation in vivo, indicating broader relevance to neurodegenerative proteopathies. By integrating in vivo functional screening with mechanistic studies in human cells, this work identifies SSH1 as a druggable phosphatase that constrains autophagy at the level of ATG9A-dependent vesicle formation.

Keywords: Autophagosome biogenesis; MAPT/tau aggregation; autophagy; flux; lysosomal degradation; phosphatase; proteopathy

DOI: https://doi.org/10.1080/15548627.2026.2752745