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. Thus, 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 leverage to efficiently control mitochondrial processes? Which mitochondrial processes are disrupted in diseases and how might these be targeted therapeutically?
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 how cells regulate mitochondrial metabolism and establish a customized mitochondrial infrastructure across tissues and in response to a changing cellular environment. Below are current focuses of our lab.
Post-transcriptional control of gene expression
Post-transcriptional regulatory processes are becoming increasingly appreciated as a means of controlling the efficiency, timing, location, and tissue specificity of gene expression. We leverage quantitative proteomics and expression profiling to identify genes subject to regulation at the mRNA level. In particular, we focus on elements in the untranslated regions (UTR) of mRNA that are involved in titrating the expression of mitochondrial proteins.
Regulation of mitochondrial function by post-translational modifications
While transcriptional and post-transcriptional processes are instrumental to mitochondrial biogenesis and restructuring, real-time regulation of protein function is generally carried out by post-translational modifications (PTMs). Much of the mitochondrial proteome is modified by PTMs such as phosphorylation and acetylation, but the proteins responsible for these modifications and their roles in regulating mitochondrial function are largely unknown. We combine molecular biology and proteomics to match mitochondrial signaling molecules with their substrates, and to explore how the cell uses PTMs to control mitochondrial function in response to cellular stresses such as hypoxia and inflammation.
Comparative mitochondrial proteomics of healthy and disease states
Faulty mitochondrial function has been implicated in ~50 monogenic disorders, and growing evidence suggests it is also a major contributor to a range of common diseases. Most notably, mitochondrial dysfunction is a central theme of type 2 diabetes mellitus (T2DM), which currently affects more than 20 million individuals in the US alone. However, the specific mitochondrial alterations that appear to play a role in the development of T2DM remain poorly defined. In collaboration with UW-Madison professors Alan Attie and Josh Coon, we are applying state-of-the-art quantitative mass spectrometry to produce a map of proteome and phospho-proteome alterations in mitochondria during the onset of diabetes.
Control of OXPHOS function and assembly
Oxidative phosphorylation (OXPHOS) is the engine that drives the bulk of ATP production in cells, and OXPHOS disorders are the most common group of inborn errors of metabolism. An array of gene mutations that give rise to OXPHOS disorders have been identified through human genetics, but many of these genes encode proteins of no known function. We use mitochondrial physiology and biochemistry to explore the role of these proteins in the proper assembly and function of the OXPHOS complexes, with the ultimate goal of identifying promising therapeutic targets for mitochondrial diseases.
Honors & Awards
- 2012 Shaw Scientist Award, The Greater Milwaukee Foundation
- 2011 Glenn Award, Glenn Foundation for Medical Research
- 2011 Searle Scholar Award, Kinship Foundation
- 2011 EllisonMedical Foundation New Scholar Award in Aging (declined)
- 2011–Hilldale Undergraduate/Faculty Research Fellowship Awards (4)
- Tagliabracci VS*, Wiley SE*, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ and Dixon JE, A single kinase generates the majority of the secreted phosphoproteome, Cell, 2015, 18;161(7):16-19-32.
- Overmyer KA, Evans CR, Qi NR, Minogue CV, Chermside-Scaboo CJ, Kock LG, Britton SL, Pagliarini DJ, Coon JJ and Burant CF, Maximal exercise oxidative capacity in male and female rats is driven by skeletal muscle mitochondrial fuel selection and protein acetylation, Cell Metabolism, 2015, 3;21(3):468-78.
- Stefely JA*, Reidenbach AG*, Ulbrich A, Oruganty K, Floyd BJ, Jochem A, Saunders JM, Johnson IE, Minogue CE, Wrobel RL, Barber GE, Lee D, Li S, Kannan N, Coon JJ, Bingman CA and Pagliarini DJ, Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable ubiquinone biosynthesis, Molecular Cell, 2015, 57: 83-94.
- Lohman DC*, Forouhar F*, Beebe ET, Stefely MS, Minogue CE, Ulbrich A, Stefely JA, Sukumar S, Luna-Sanchez M, Lew S, Seetharaman J, Xiao R, Wang H, Wrobel RL, Everett JK, Mitchell JC, Lopez LC, Coon JJ, Tong L† and Pagliarini DJ†, Mitochondrial COQ9 is a lipid binding protein that associates with COQ7 to enable coenzyme Q biosynthesis, Proceedings of the National Academy of Sciences, 2014, 111(44):E4697-705 (Direct submission)
- Khadria AS, Mueller BK, Stefely JA, Tan CH, Pagliarini DJ† and Senes A†, A Gly-zipper motif mediates homo-dimerization of the transmembrane domain of the mitochondrial kinase ADCK3, Journal of the American Chemical Society, 2014, 136, 14068-77