bims-tofagi 2026-03-22 papers

Issue of 2026–03–22
three papers selected by
Michele Frison, University of Cambridge

Nat Commun. 2026 Mar 14.

MFF budding from mitochondria regulates melanosome size and maturation.

Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.

Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.

DOI: https://doi.org/10.1038/s41467-026-70572-3

Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00037-1. [Epub ahead of print]89 102147

Quantitative imaging of mitochondrial redox conditions at the single-organelle level.

Steffen Pöschel, Michael Müller.

Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.

Keywords: 2-photon microscopy; Aging; Hypoxia; Mitochondria; Reactive oxygen species; Redox imaging; roGFP

DOI: https://doi.org/10.1016/j.mito.2026.102147

Cell Death Dis. 2026 Mar 15.

O-GlcNAcylation of YAP1 promotes lung transplant ischemia-reperfusion injury via binding to HIF1α transcription factor and activating autophagy and mitophagy.

Shaohua Dai, Xuemei Wan, Lingchun Xia, Lei Xu, Chunfan Xie, Guohui Wang, Jian Tang.

Lung transplant ischemia-reperfusion injury poses a significant challenge in transplantation medicine, often causing severe complications and poor patient outcomes. Our study focused on the role of O-GlcNAcylation of Yes-associated protein 1 (YAP1) in exacerbating this injury by regulating autophagy and mitochondrial autophagy pathways. We found that hypoxia-reoxygenation robustly activated the Hippo-YAP1 signaling pathway, leading to increased damage in lung epithelial cells. Concurrently, autophagy and mitochondrial autophagy levels were significantly upregulated, indicating cellular stress responses. During actual lung transplantation, ischemia-reperfusion resulted in a marked increase in autophagy and mitochondrial autophagy levels, accompanied by elevated tissue damage. Notably, YAP1 played a crucial role in orchestrating these processes, as its knockdown reduced autophagy and mitochondrial autophagy levels under both hypoxia-reoxygenation and ischemia-reperfusion conditions. We further elucidated that OGT-mediated O-GlcNAc modification of YAP1 enhanced its interaction with HIF1α, activating downstream hypoxia-responsive molecules. Knockdown of the key enzyme OGT significantly mitigated autophagy, mitophagy, and associated damage in lung epithelial cells and transplant tissues subjected to hypoxia-reoxygenation and ischemia-reperfusion. These findings reveal the intricate interplay between O-GlcNAcylation of YAP1, HIF1α binding, autophagy activation, and mitochondrial autophagy in driving lung transplant ischemia-reperfusion injury, suggesting potential therapeutic targets for ameliorating its detrimental effects.

DOI: https://doi.org/10.1038/s41419-026-08548-w