bims-mitpro 2026-03-29 papers

Issue of 2026–03–29
four papers selected by
Andreas Kohler, Umeå University

Autophagy. 2026 Mar 22. 1-2

Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.

Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.

Keywords: Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control

DOI: https://doi.org/10.1080/15548627.2026.2646238

Protein Sci. 2026 Apr;35(4): e70537

From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family.

Catherine S Palmer, Phoebe J Leeming, Diana Stojanovski.

Mitochondrial carrier proteins are essential for cellular physiology as they are active in a wide range of metabolic pathways including production of cellular energy, amino acid synthesis, redox balance and ion homeostasis. The double membrane of mitochondria provides a tightly gated environment through which carrier proteins facilitate the exchange of substrates including nucleotides, ions, metabolites, cofactors and vitamins. The biogenesis of the carrier family relies on the coordinated action of the TOM and TIM22 complexes, which direct the translocation of nuclear-encoded precursors across the outer membrane (TOM) and their integration into the mitochondrial inner membrane (TIM22). Due to the intrinsic hydrophobicity of the carrier precursors, their import pathway requires chaperones in both the cytosol and intermembrane space to maintain solubility and prevent aggregation during transit. Given their central role in metabolism, dysfunction of the biogenesis machinery or the carrier proteins has serious consequences to human health. In this review we summarize the current understanding of carrier protein biogenesis in human cells and highlight how perturbations to this pathway influence human health.

Keywords: SLC25; TIM; TOM; citrin deficiency; mitochondrial carrier protein; protein biogenesis

DOI: https://doi.org/10.1002/pro.70537

Front Cell Dev Biol. 2026 ;14 1761278

Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.

Qing Chen, Yu-Lun Chang, Miao-Wen Hung, Po-Lin Lee, Chen Hsin, Yi-Fan Lin.

Introduction: The decline of mitochondrial homeostasis and proteostasis, the two key cell quality control mechanisms, is the hallmark of aging and age-related diseases. One of the most notable examples is the age-related progressive loss of muscle mass, quality, and strength --a condition known as sarcopenia. In atrophic muscle, mitochondrial dysfunction and proteostasis impairment frequently occur together, indicating a potential association between the decline of mitochondrial homeostasis and proteostasis. However, the mechanism by which these two modes of cell quality control are coordinated remains poorly understood.
Methods: We employed dexamethasone-induced muscle atrophy models in both larval and adult zebrafish to investigate the role of cell stress responses in muscle maintenance. Mitochondrial stress was assessed by measuring the mitochondrial unfolded protein response (UPRmt) activity using qRT-PCR and reporter analyses. Proteostasis impairment was evaluated by detecting insoluble polyubiquitinated protein aggregates via Western blotting. Muscle integrity was examined histologically in larval and adult tissues. We performed these assays in sirt1 loss of function conditions (genetic mutation and pharmacological inhibition). Furthermore, to elucidate the mechanism by which Sirt1 regulates proteostasis and muscle preservation, we inhibited the mitochondrial fatty acid oxidation (mFAO) using etomoxir.
Results: Inhibition of Sirt1 markedly exacerbated muscle deterioration and proteostasis impairment under dexamethasone-induced muscle atrophy in zebrafish. Mechanistically, Sirt1 is required for activation of the UPRmt, which in turn promotes expression of the mFAO gene cpt1b. Pharmacological inhibition of Cpt1 using etomoxir phenocopied the defects in muscle integrity and proteotoxic stress observed following Sirt1 inhibition. Importantly, enhancement of proteostasis via hormetic heat shock partially rescued the etomoxir-induced muscle defects.
Discussion: We have demonstrated that muscle atrophic stress induced by dexamethasone treatment activates the UPRmt in zebrafish. The UPRmt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Notably, suppressing the UPRmt via Sirt1 inhibition leads to protein aggregation and the ultimate loss of muscle mass, indicating a link between mitochondrial function and proteostasis. We have further shown that mitochondrial metabolism plays a role in proteostasis regulation, as pharmacological inhibition of the mFAO exacerbates dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking UPRmt signaling to myocellular proteostasis, and highlight the activity of Sirt1, which coordinates these two key cell quality control mechanisms, in muscle preservation during muscle atrophy.

Keywords: SIRT1; UPRmt; mitochondrial dysfunction; mitochondrial homeostasis; muscle atrophy; myocellular proteostasis; proteostasis

DOI: https://doi.org/10.3389/fcell.2026.1761278

EMBO J. 2026 Mar 24.

Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.

Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.

Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.

Keywords: AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis

DOI: https://doi.org/10.1038/s44318-026-00734-y