PT  - JOURNAL ARTICLE
AU  - Yuhao Wang
AU  - Linhao Ruan
AU  - Jin Zhu
AU  - Xi Zhang
AU  - Alexander Chih-Chieh Chang
AU  - Alexis Tomaszewski
AU  - Rong Li
TI  - Metabolic regulation of misfolded protein import into mitochondria
AID  - 10.1101/2023.03.29.534670
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.03.29.534670
4099  - http://biorxiv.org/content/early/2023/03/29/2023.03.29.534670.short
4100  - http://biorxiv.org/content/early/2023/03/29/2023.03.29.534670.full
AB  - Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the ‘mitochondria as guardian in cytosol’ (MAGIC) whereby cytosolic misfolded proteins are imported into and degraded inside mitochondria. In this study, a genome-wide screen in yeast uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of misfolded proteins into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by misfolded proteins such as those associated with neurodegenerative diseases.Competing Interest StatementThe authors have declared no competing interest.