bims-smemid 2026-04-26 papers

Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166

Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.

Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.

Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.

Keywords: Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes

DOI: https://doi.org/10.1016/j.redox.2026.104166

Protein Sci. 2026 May;35(5): e70553

Proteolytic control of mitochondrial protein translocases.

Lara Kroczek, Thomas Langer.

Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.

Keywords: mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control

DOI: https://doi.org/10.1002/pro.70553

J Am Chem Soc. 2026 Apr 21.

A Deep-Red-Absorbing Osmium(II)-Based Photosensitizer Evokes Pyroptosis by Targeting Glutamine Metabolism and Impairing Cell Redox Homeostasis.

Yiyi Zhang, Zhimei Xiao, James W Southwell, Ruonan Gao, Bruno Saubaméa, Morgane Moinard, Philippe Arnoux, Céline Frochot, Pierre Mesdom, Gilles Gasser.

Pyroptosis plays an emerging role in cancer immunotherapy, however, most currently known compounds that activate this cell death mechanism were discovered serendipitously. Here, we report a pyroptosis-inducing strategy that works through metabolic reprogramming of cancer cells to enhance antitumor immunity. Specifically, an osmium-based photosensitizer (Os) was covalently attached to a small-molecule glutamine carrier protein inhibitor (IMD-0354), to construct the conjugate Os-IMD. This conjugate significantly enhanced the photosensitizer's uptake into cancer cells via the glutamine metabolic pathway, inhibited glutamine uptake, and promoted mitochondrial targeting. As a result, upon light irradiation, Os-IMD induced mitochondrial damage and impaired electron transport chain function as well as intracellular redox homeostasis, leading to a switch in the mode of cell death from the apoptosis typically observed with Os to gasdermin D (GSDMD)-mediated pyroptosis. Our study offers a new avenue for the development of scalable pyroptosis-inducing agents.

DOI: https://doi.org/10.1021/jacs.6c04446