Mitochondrial proteins, pathways and pathogenesis
Mitochondria are complex organelles whose dysfunction underlies a broad spectrum of human diseases. Mitochondria house a wide range of metabolic pathways, and are central to apoptosis, ion homeostasis and reactive oxygen species production. As such, to maintain cellular homeostasis cells must exert careful control over their mitochondrial composition and function.
How do cells custom-build mitochondria to suit their metabolic needs? What mechanisms do cells use to efficiently control mitochondrial processes? Which mitochondrial processes are disrupted in diseases and how might these be targeted therapeutically? What are the functions of disease-related orphan mitochondrial proteins?
Our lab takes a multi-disciplinary approach to investigating these questions. By integrating classic biochemistry, molecular biology and genetics with large-scale proteomics and systems approaches, we aim to elucidate the biochemical underpinnings of mitochondrial dysfunction in human disease. Below are current focuses of our lab. Pagliarini_Cell.pdf
Our work has revealed that mitochondria are replete with proteins harboring post-translational modifications (PTMs)whose abundances change significantly under contrasting biological states. We are now elucidating how these PTMs affect the activities of select mitochondrial proteins and are characterizing enzymes in mitochondria that regulate PTM abundance.
Grimsrud_Cell Met.pdf, Still_JBC.pdf
Mitochondria vary considerably in composition across tissues and remodel to meet cellular needs. Recently, we discovered that cellular iron levels convey a type of rheostat control over mitochondrial protein content and oxidative capacity via a unique mechanism. Our work is setting a foundation for new approaches to manipulating mitochondrial form and function in human health and disease. Rensvold_Cell Rep.pdf
Orphan mitochondrial proteins
Hundreds of mitochondrial proteins have no established biochemical function, including many associated with human disease. As such, elucidation of these functions has become a major bottleneck in understanding mitochondrial function and pathophysiology. To address this, we use large-scale experimental and computational approaches to systematically annotate these disease-related “orphan” mitochondrial proteins (OMPs), and then apply rigorous molecular and structural biology methods to establish the specific functions of select proteins at biochemical depth.
Pagliarini_Cell.pdf, Pagliarini_Genes Dev.pdf
Coenzyme Q biosynthesis
Coenzyme Q (CoQ) is a requisite component of the mitochondrial oxidative phosphorylation machinery—discovered at UW-Madison more that 50 years ago—whose deficiency is associated with multiple human diseases. CoQ biosynthesis involves multiple unexplained steps, and includes multiple OMPs with no clear biochemical role in the pathway. We are integrating various biochemical, genetic and structural biology approaches to further elucidate the steps of this essential pathway.
Lohman_PNAS.pdf, Stefely_Mol Cell.pdf, Khadria_JACS.pdf