Year: 2026
Type: article
Abstract: Mitochondrial proteotoxic stress activates the mammalian UPR mt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import‐gated sensing logic: reduced preprotein import and mito–nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria‐targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone–protease capacity while transiently reducing the nuclear‐encoded OXPHOS load. Parallel translational mechanisms that include eIF2α‐dependent repression, stress‐granule triage, and miRNA‐driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1‐ and CLPP‐dependent proteolysis, mitoribosome pausing, and tRNA‐processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPR mt loci. Together, these import‐gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.
Source: FEBS Journal
DOI: 10.1111/febs.70607
Institutions: University of Wrocław, University of Alabama at Birmingham
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funder: Narodowe Centrum Nauki
Award: G6060517246
OpenAlex ID: W7162870436