Language
English
Publication Date
6-5-2026
Journal
Nature Communications
DOI
10.1038/s41467-026-73841-3
PMID
42248849
PMCID
PMC13396219
PubMedCentral® Posted Date
6-5-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling becomes essential during stress adaptation. In an acute liver-injury model, Amcf1 knock-in mice were fully protected, exhibiting elevated OPA1, reduced caspase-3 and PARP activation, and preserved Beclin 1. This functional duality reflects AMC-F1's ability to modulate the mitochondrial integrated stress response (mtISR), enabling adaptive ATF4 signaling while preventing maladaptive responses when stress exceeds a threshold. Autophagy upregulation by AMC-F1 is critical for fine-tuning the ISR and preserving cellular resilience. Together, our findings position AMC-F1 as a stress-responsive gatekeeper and a novel coordinator of mitochondrial-autophagy crosstalk, defining a cellular state primed for stress adaptation.
Keywords
Animals, Autophagy, Mitochondria, Mice, Stress, Physiological, Mitochondrial Proteins, Mice, Knockout, Integrated Stress Response, Activating Transcription Factor 4, GTP Phosphohydrolases, Beclin-1, Energy Metabolism, Signal Transduction, Gene Knock-In Techniques, Mice, Inbred C57BL, Mitochondria, Autophagy, Cancer epidemiology
Published Open-Access
yes
Recommended Citation
Wang, Yuqin; Rao, Raksha K; Vu, Trung; et al., "AMC-F1 Regulates Mitochondria-Autophagy Crosstalk Independent of Nutrient Stress" (2026). The Brown Foundation: Institute of Molecular Medicine. 126.
https://digitalcommons.library.tmc.edu/molecular_med/126