BIOCHEMISTRY

​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.

Systematic functional annotation of the mitochondrial proteome

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, and then apply rigorous molecular and structural biology methods to establish the specific functions of select proteins at biochemical depth.

Selected recent manuscripts led/co-led by our lab: Lapointe CP et al. Cell Systems, 2018;
Jha et al. Cell Systems, 2018a; Jha et al. Cell Systems, 2018b; Floyd BJ et al. Molecular Cell, 2016; Pagliarini et al., Cell, 2008

Elucidating the mechanisms of 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 proteins 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.

Selected recent manuscripts led/co-led by our lab: Lohman DC et al. Molecular Cell, 2019; Reidenbach AG et al. Cell Chemical Biology, 2018; Veling MT et al. Molecular Cell, 2017; Stefely JA et al. Molecular Cell, 2016; Stefely JA et al. Molecular Cell, 2015; Lohman DC et al. Proceedings of the National Academy of Sciences, 2014; Khadria AS et al. Journal of the American Chemical Society, 2014

Regulation of mitochondrial function and biogenesis

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.

Selected recent manuscripts led/co-led by our lab: Niemi NM et al. Nature Communications, 2019; Guo X et al. Journal of Biological Chemistry, 2017; Guo X et al. Cell Reports, 2017;
Still AJ et al.  Journal of Biological Chemistry, 2013; Rensvold JW et al. Cell Reports, 2013; Grimsrud PA et al. Cell Metabolism, 2012