Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States; Biochemistry, Cellular and Molecular Biology (BCMB) Graduate Program, Johns Hopkins University School of Medicine, Baltimore, United States
Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
Jin Zhu
Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore, Singapore
Xi Zhang
Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
Alexander Chih-Chieh Chang
Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, United States
Alexis Tomaszewski
Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States; Biochemistry, Cellular and Molecular Biology (BCMB) Graduate Program, Johns Hopkins University School of Medicine, Baltimore, United States
Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States; Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore, Singapore; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, United States
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 (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs 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 MPs such as those associated with neurodegenerative diseases.
