AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology

Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alter-ations 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 mito-chondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochon-drial 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 con-trols 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 trans-ducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.

Automated summary

This study identifies MTFR1L as a critical mitochondrial protein that transduces AMPK-dependent metabolic changes through regulation of mitochondrial dynamics. The phosphorylation of MTFR1L by AMPK controls its function in regulating mitochondrial morphology and stress-induced AMPK-dependent mitochondrial fragmentation.