Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1 Malik 2023

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https://www.science.org/doi/10.1126/science.abj5559

Abstract
Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate–activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)–FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1–dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.


CONCLUSION
Our data establish FNIP1 as the long-sought substrate of AMPK that controls TFEB translocation to the nucleus, defining AMPK phosphorylation of FNIP1 as a singular event required for increased lysosomal and mitochondrial gene expression programs after metabolic stresses. This study also illuminates the larger biological question of how mitochondrial damage triggers a temporal response of repair and replacement of damaged mitochondria: Within early hours, AMPK-FNIP1–activated TFEB induces a wave of lysosome and autophagy genes to promote degradation of damaged mitochondria, and a few hours later, TFEB–up-regulated PGC1⍺ and ERR⍺ promote expression of a second wave of genes specifying mitochondrial biogenesis. These insights open therapeutic avenues for several common diseases associated with mitochondrial dysfunction, ranging from neurodegeneration to type 2 diabetes to cancer.

 

https://twitter.com/user/status/1650039247880036354

 

CRACKING THE CASE OF MITOCHONDRIAL REPAIR AND REPLACEMENT IN METABOLIC STRESS

Salk scientists find protein FNIP1 links cellular powerhouse damage to repair during metabolic stress, with broad disease implications spanning from diabetes to cancer to neurodegeneration

https://www.salk.edu/news-release/c...l-repair-and-replacement-in-metabolic-stress/