David J. Pagliarini

Associate Professor, Department of Biochemistry; with the Morgridge Institute for Research Lab Website pagliarini@wisc.edu(608) 316-4664

2268 Morgridge Institute for Research
330 North Orchard Street
Madison, WI 53715-1119

Education

B.S., University of Notre Dame
Ph.D., University of California, San Diego
Postdoctoral, Harvard Medical School

Mitochondrial proteins, pathways, and pathogenesis

Images of mitochondriaMitochondria 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 2016 Molecular Cell cover 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
*IPiB student

Elucidating the mechanisms of coenzyme Q biosynthesis
Coenzyme Q (CoQ) is a requisite component of the mitochondrial 2018 Cell Chemical Biology cover 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
*IPiB student

Regulation of mitochondrial function and biogenesis
Our work has revealed that mitochondria are replete with proteins 2013 Cell Reports cover 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
*IPiB student

Phot of David Pagliarini

Areas of Expertise

  • Biomolecular Folding & Interactions
  • Cell Structure & Signaling
  • Chemical Biology & Enzymology
  • Membrane Dynamics & Proteins
  • Metabolism & Endocrinology
  • Quantitative Biology
  • Systems & Synthetic Biology