bims-tofagi 2026-05-10 papers

Issue of 2026–05–10
four papers selected by
Michele Frison, University of Cambridge

J Biol Chem. 2026 May 06. pii: S0021-9258(26)02000-4. [Epub ahead of print] 113128

The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.

Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt.

Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.

Keywords: (10): mitochondria; PINK1; Parkin; aging; autophagy; biomarker; mitophagy; neurodegeneration; phospho-ubiquitin; proteasome

DOI: https://doi.org/10.1016/j.jbc.2026.113128

Autophagy. 2026 May 06. 1-3

ROS-driven mitophagy arrest mediates the anti-glioblastoma activity of Molephantin.

Zhipeng Ling, Junliang Li, Guocai Wang, Yubo Zhang, Jun-Ping Pan.

Mitophagy, the selective autophagic degradation of mitochondria, often acts as a pro-survival mechanism in tumor cells, including Glioblastoma (GBM), by clearing damaged mitochondria and mitigating oxidative stress. GBM is a highly aggressive brain tumor characterized by profound resistance to conventional therapies. Our recent study identified Molephantin (EM-5), a natural small molecule capable of crossing the blood-brain barrier, as a potent anti-GBM agent. Mechanistically, EM-5 triggers severe mitochondrial dysfunction and massive reactive oxygen species (ROS) production in GBM. Crucially, we discovered that EM-5 acts as a novel late-stage mitophagy inhibitor. It specifically blocks the fusion of mitophagosomes with lysosomes without affecting early autophagosome formation or lysosomal acidification. This ROS-driven fusion defect leads to the toxic accumulation of damaged mitochondria, thereby amplifying oxidative stress and driving GBM cells into apoptosis. Collectively, our work establishes that targeting late-stage mitophagy flux via ROS modulation is a valuable paradigm for the discovery and development of therapeutic agents against GBM.

Keywords: Autophagosome-lysosome fusion; Molephantin; glioblastoma; mitophagy; reactive oxygen species

DOI: https://doi.org/10.1080/15548627.2026.2668084

Chem Biol Interact. 2026 May 05. pii: S0009-2797(26)00231-0. [Epub ahead of print] 112123

Significance of mitophagy in reactive oxygen species-dependent neuronal apoptosis triggered by pyrrolidinophenones.

Yuji Sakai, Yoshifumi Morikawa, Shunsuke Jimbo, Koichi Suenami, Emiko Yanase, Akira Ikari, Toshiyuki Matsunaga.

Pyrrolidinophenones (PPs), a class of synthetic cathinones, have emerged as hazardous new psychoactive substances due to their high lipophilicity and potent neurotoxicity. However, the mechanisms underlying PPs-induced neuronal damage, particularly the roles of mitochondrial reactive oxygen species (ROS) and mitophagy, remain unclear. In this study, we investigated the interplay among ROS overproduction, mitochondrial dysfunction, mitophagy, and apoptosis in human neuronal cells exposed to representative PPs. Treatment with PPs induced neuronal cell toxicity in a manner dependent on the elongation of the alkyl chain, with α-pyrrolidinooctanophenone (POP) exhibiting the strongest effects. The treatment also facilitated the production of intracellular and mitochondrial ROS, including superoxide, hydrogen peroxide, and hydroxyl radical. Furthermore, the cytotoxicity was remarkably attenuated by pretreating with antioxidant, N-acetyl-L-cysteine, indicating a critical role of ROS in PPs-induced cytotoxicity. Subcellular fractionation analysis revealed an accumulation of highly lipophilic PPs such as α-pyrrolidinoheptanophenone (PHPP) and POP in mitochondria, and the treatment with PHPP or POP resulted in an increase in Bax/Bcl2 ratio, caspase-9 activation, and mitochondrial lipid peroxidation, presumably due to an activation of mitochondria-dependent apoptotic signaling. Notably, POP induced mitophagy via activation of the PINK1/Parkin pathway. Additionally, pharmacological inhibition of autophagy or mitophagy exacerbated both ROS production and cytotoxicity, suggesting a protective role of mitophagy through the removal of damaged mitochondria. Collectively, these findings demonstrate that mitochondrial accumulation of PPs promotes ROS-dependent apoptosis, while mitophagy functions as an adaptive cytoprotective mechanism. This study provides new insights into mitochondrial quality control in PPs-induced neurotoxicity and highlights mitophagy as a potential therapeutic target.

Keywords: Apoptosis; Mitophagy; Neuronal SK-N-SH cell; Pyrrolidinophenones; Reactive oxygen species

DOI: https://doi.org/10.1016/j.cbi.2026.112123

Redox Biol. 2026 Apr 30. pii: S2213-2317(26)00193-X. [Epub ahead of print]94 104195

Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.

Lianne Jhc Jacobs, Sebastian Doll, Dietrich Trümbach, Matteo Veronese, Giada Di Pietro, Fatma Isil Yapici, Lidwina Hasberg, Pascal Gentzsch, Sarah Gerlich, Jens Hansen, Silvia von Karstedt, Elena I Rugarli, Marcus Conrad, Armindo Salvador, Jan Riemer.

Hydrogen peroxide (H2O2) plays a dual role as both a signalling molecule and a mediator of oxidative stress. Although mitochondria are major producers of H2O2, the relative contributions of mitochondrial versus cytosolic antioxidant systems to mitochondrial H2O2 homeostasis in intact cells remain poorly defined. Here, we combined compartment-resolved live-cell imaging using HyPer7, inducible mitochondrial H2O2 generation (matrix-targeted d-amino acid oxidase), kinetic modelling, and a targeted CRISPR/Cas9 screen to dissect determinants of mitochondrial H2O2 dynamics in HEK293 cells. Unexpectedly, we found that the cytosolic peroxiredoxin PRDX1 is a dominant regulator of mitochondrial matrix H2O2 levels. Loss of cytosolic PRDXs markedly enhanced matrix Hyper7 signals under both exogenous and mitochondria-intrinsic H2O2 production, exceeding the effects of deleting mitochondrial peroxiredoxins. Modelling and transport experiments indicated a very high permeability of the mitochondrial inner membrane to H2O2 enabling rapid efflux and the establishment of steep concentration gradients. This permits the cytosol to function as a major sink to limit matrix H2O2 accumulation. PRDX1 deficiency sensitized cells to chronic mitochondrial oxidative stress. A targeted CRISPR screen identified the Rab7 GAP TBC1D5, linking mitophagy to cellular survival under these conditions. Consistently, PRDX1/2-deficient cells exhibited elevated mitophagic flux, indicating mitochondrial quality control as a compensatory response. Our study reveals that cytosolic PRDXs critically impact mitochondrial redox homeostasis and provides a systems-level framework for understanding compartmental redox control and stress adaptation.

DOI: https://doi.org/10.1016/j.redox.2026.104195