Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1

摘要

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 autoph-agy genes to promote degradation of damaged mitochondria, and a few hours later, TFEB-up-regulated PGC1α and ERRα 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.