bims-tofagi 2026-01-11 papers

Issue of 2026–01–11
five papers selected by
Michele Frison, University of Cambridge

J Cell Biol. 2026 Mar 02. pii: e202507084. [Epub ahead of print]225(3):

A Rab1 interactome illuminates a dual role in autophagy and membrane trafficking.

Alexander R van Vliet, Alison K Gillingham, Tomos E Morgan, Yohei Ohashi, Tom S Smith, Ferdos Abid Ali, Sean Munro.

The small GTPase Rab1 is found in all eukaryotes and acts in both ER-to-Golgi transport and autophagy. Several Rab1 effectors and regulators have been identified, but the mechanisms by which Rab1 orchestrates these distinct processes remain incompletely understood. We apply MitoID, a proximity biotinylation approach, to expand the interactome of human Rab1A and Rab1B. We identify new interactors among known membrane traffic and autophagy machinery, as well as previously uncharacterized proteins. One striking set of interactors are the cargo receptors for selective autophagy, indicating a broader role for Rab1 in autophagy than previously supposed. Two cargo receptor interactions are validated in vitro, with the Rab1-binding site in optineurin being required for mitophagy in vivo. We also find an interaction between Rab1 and the dynein adaptor FHIP2A that can only be detected in the presence of membranes. This explains the recruitment of dynein to the ER-Golgi intermediate compartment and demonstrates that conventional methods can miss a subset of effectors of small GTPases.

DOI: https://doi.org/10.1083/jcb.202507084

Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00492-6. [Epub ahead of print]89 103979

Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.

William M Curtis, Patrick C Bradshaw.

The mechanism of selecting dysfunctional mitochondria for mitophagy is only partially understood. Evidence suggests the mechanism involves reactions of superoxide (O2-•), hydrogen peroxide (H2O2), nitric oxide (NO•), peroxynitrite (ONOO-), carbonate radicals (•CO3-), nitrogen dioxide radicals (•NO2), hydroxyl radicals (•OH), oxygen (•O2• or O2), and carbon dioxide (CO2). However, the larger picture of how these reactions are organized to induce mitophagy is unclear. Extensive evidence suggests that increased mitochondrial matrix O2-• is associated with the mitophagy of dysfunctional organelles. In most cells, mitochondrial O2-• is mainly produced by the reaction of O2 with free radical intermediate forms of coenzyme Q (CoQ) and flavins, which are generated in substantial amounts in the inner membrane and matrix space of dysfunctional mitochondria. Mitochondrial O2-• plays two key roles in orchestrating mitophagy. First, it is dismutated by mitochondrial matrix superoxide dismutase 2 (SOD2) to H2O2. This diffusible messenger directs the nuclear and cytoplasmic compartments to prepare for mitophagy, including the generation of cytoplasmic NADPH and glutathione and the increased synthesis of membrane-diffusible NO•. Second, mitochondrial matrix space O2-• readily reacts with NO• to form ONOO-, which initiates a cascade of free radical reactions culminating in mitochondrial membrane depolarization and PINK1 and Parkin-driven mitophagy. Compelling observations that support the proposed mechanism are given. This mechanism could be targeted for the treatment of diseases characterized by dysfunctional mitophagy, such as Parkinson's disease. Because of the central role of mitochondrial O2-• as a sentinel for selective mitophagy, we have named this hypothesis the superoxide sentinel hypothesis of mitochondrial quality control.

Keywords: DJ-1; Mitophagy; NADPH; Nitric oxide synthase; Parkinson's disease; Superoxide sentinel hypothesis

DOI: https://doi.org/10.1016/j.redox.2025.103979

Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2516471123

USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy.

Yanqi Xu, Keshuo Jin, Jiaqing Chen, Zhongding Li, Zhenhu Zhu, Xian Su, Jiangyun Shen, Bincheng Zhou, Zijun Cao, Liyan Lou, Deyu Deng, Jianzhao Zhang, Baohua Liu, Yangping Shentu, Xu Wang.

Parkinson's disease (PD) is a progressive neurodegenerative disease that casts a significant shadow over global health and the identification of therapeutic targets for PD will empower more effective clinical treatment. The gene encoding the deubiquitinating enzyme USP25 has been identified as a susceptible locus for PD, but the role of USP25 in PD remains unknown. In this study, we found that USP25 exacerbated dopaminergic neuronal loss and motor deficits in murine models of PD by sabotaging the mitophagy machinery. USP25 physically interacted with the autophagy receptor optineurin and disrupted its linkage with K63-specific polyubiquitin chains, leading to impaired mitophagy and the accumulation of damaged mitochondria. Genetic ablation or pharmacological inhibition of USP25 significantly restored mitophagy and thereby impeded the neurodegenerative progression in PD model mice. Collectively, our results unravel a pivotal role of USP25 in PD and identify USP25 as a pharmacological target for the development of PD drugs.

Keywords: Parkinson’s disease; USP25; mitophagy; optineurin; ubiquitination

DOI: https://doi.org/10.1073/pnas.2516471123

Cell Res. 2026 Jan;36(1): 11-37

Mitophagy in the pathogenesis and management of disease.

Qi Wang, Yu Sun, Terytty Yang Li, Johan Auwerx.

Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy - from receptors and stress-responsive triggers to lysosomal degradation - illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.

DOI: https://doi.org/10.1038/s41422-025-01203-7

NPJ Metab Health Dis. 2026 Jan 06. 4(1): 1

Parkin-ACSL4 axis in ferroptosis regulation: a narrative review on therapeutic insights from exercise in aging cardiomyocytes.

Negin Kordi, Behnam Bagherzadeh-Rahmani, Rezvan KheirAndish, Raheleh Rezaali, Brent R Stockwell.

Ferroptosis, iron-dependent regulated cell death, drives age-related cardiac dysfunction. This review examines aerobic exercise modulation of ferroptosis in aging cardiomyocytes via Parkin-ACSL4 axis. Parkin promotes ACSL4 ubiquitination/degradation, reducing lipid peroxidation and ROS. Exercise activates PINK1/Parkin mitophagy and hepcidin, enhancing mitochondrial resilience and iron homeostasis. Despite promising preclinical evidence, molecular mechanisms remain unclear. Aerobic exercise offers non-pharmacological cardiac protection against ferroptosis in aging.

DOI: https://doi.org/10.1038/s44324-025-00092-z