Regulation of Mitochondrial Metabolism by Reversible Phosphorylation

Abstract

Mitochondria are centers of metabolism whose activities need to be calibrated to meet changing cellular needs. General dysfunction of these organelles is implicated in many common human disorders, including Parkinson's, Alzheimer's, various cancers, metabolic syndrome, type 2 diabetes, obesity, non‐alcoholic fatty liver disease, heart failure, and general metabolic inflexibility, most often through unclear means. Defining the pathogenic mitochondrial alterations that contribute to these metabolic disorders and devising new therapeutic strategies to rectify them represent principal challenges in mitochondrial medicine. A potential contributor to this dysfunction is aberrant intra‐mitochondrial protein phosphorylation—a process recognized as critical for pyruvate dehydrogenase regulation for more than 50 years, but relatively unexplored otherwise. Recent efforts from our laboratories and others have now revealed that mitochondrial proteins are replete with dynamic phosphorylation that changes reproducibly between healthy and diseased states, and that phosphorylation can alter the activities of proteins involved in core metabolic pathways. We have also now connected select phosphorylation events to poorly characterized matrix protein phosphatases, thereby beginning to establish a mechanistic framework for understanding mitochondrial protein phosphorylation and its effects on metabolic processes. Given these emerging findings, we hypothesize that reversible phosphorylation may be widely important in calibrating mitochondrial metabolism, and that its mismanagement could contribute to the pathophysiology of mitochondria‐related disorders. To explore this, we combine mammalian physiology, omics‐level analyses, and classical biochemistry to make definitive connections between mitochondrial phosphatases and their substrates, and to establish a broad framework for understanding the role of this post‐translation modification in calibrating mitochondrial activities.Support or Funding InformationR01DK098672This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.