Wiring the powerhouse: Systems‐to‐structure approaches for defining mitochondrial protein function

Mitochondria—epicenters of cellular metabolism and bioenergetics—are much less well understood than their iconic “powerhouse” moniker implies. Hundreds of mitochondrial proteins remain uncharacterized, classic pathways include many steps not yet assigned to specific enzyme functions, a large percentage of mitochondrial diseases remain unresolved, and there are no approved FDA drugs to combat mitochondrial dysfunction. The goal of my research program is to produce a more complete understanding of mitochondrial biology by systematically establishing the functions of orphan mitochondrial proteins and their roles within disease‐related processes. We begin by devising multi‐dimensional analyses designed to make new connections between these proteins and established pathways and processes. We then employ mechanistic and structural approaches to define the functions of select proteins at biochemical depth. This ‘systems biochemistry’ strategy is helping us address outstanding biological questions, including: Which orphan mitochondrial proteins fulfill missing steps in classic mitochondrial processes, such as the biosynthesis of coenzyme Q and the assembly of complex I, and how do they operate mechanistically? And, which resident signaling proteins direct the post‐translational regulation of mitochondrial activities? In answering these and other questions, we aim to help transform the mitochondrial proteome from a component list into a metabolic circuitry of connected functions, and to establish the biochemical underpinnings of mitochondrial dysfunction in human disease.