AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology
Lisa Tilokani, Fiona M. Russell, Stevie Hamilton, Daniel M. Virga, Mayuko Segawa, Vincent Paupe, Anja V. Gruszczyk, Margherita Protasoni, Luis Carlos Tábara, Mark Johnson, Hanish Anand, Michael P. Murphy, D. Grahame Hardie, Franck Polleux, Julien Prudent
Abstract
Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.