Our research is focused on identifying novel regulators of the mitochondrial respiratory chain (MRC) to understand the molecular basis of mitochondrial dysfunction in human disorders. Many genes required for building the MRC have not been characterized, and mutations in these genes result in rare genetic disorders for which no therapy exists. We use integrative genomic approaches to discover novel mitochondrial disease genes.
Mitochondrial respiratory chain biogenesis
To systematically discover novel MRC biogenesis proteins, we use an integrative approach based on clues from evolutionary history, human genetics, and organelle proteomics to shortlist a subset of uncharacterized mitochondrial proteins that are conserved between yeast and humans. We predict that many of these proteins are involved in fundamental functions of mitochondria, including energy production by the MRC. Utilizing the tools of biochemistry, genetics, and genomics, we assign functions to these orphan proteins that may act in any step of MRC biogenesis, including mitochondrial DNA expression, addition of cofactors to the MRC apoenzymes, and formation of MRC supercomplexes. Using this approach, we have discovered a family of proteins required for copper delivery to the MRC complex. By utilizing yeast, zebrafish, and human cellular models, we have elucidated the role of mitochondrial copper metabolism in MRC biogenesis, mitochondrial bioenergetics, organismal development, and human disease pathogenesis.
S. Soma, M. N. Morgada, M. T. Naik, A. Boulet, A. A. Roesler, N. Dziuba, A. Ghosh, Q. Yu, P. A. Lindahl, J. B. Ames, S. C. Leary, A. J. Vila, V. M. Gohil, COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase. Cell Rep. 29, 4114–4126 (2019).
Phospholipid requirements for mitochondrial function
The role of phospholipids in maintaining the structural and functional integrity of the MRC remains poorly understood. Although the MRC is located in the inner mitochondrial membrane, it is not fully understood how the unique lipid milieu of the mitochondrial membrane influences the assembly and activity of the MRC. We have constructed yeast mutants with defined perturbations in mitochondrial phospholipid compositions to systematically determine the role of each of the three major phospholipids—phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL)—and their precursors in MRC assembly and activity. We have recently used these mutants as surrogate systems to dissect the phospholipid requirements of human inner mitochondrial membrane proteins, including the mitochondrial calcium uniporter. This work uncovers biochemical underpinnings of the pathology associated with Barth syndrome, a rare mitochondrial disorder of cardiolipin metabolism.
W. B. Ball, C. D. Baker, J. K. Neff, G. L. Apfel, K. A. Lagerborg, G. Zun, U. Petrovic, M. Jain, V. M. Gohil, Ethanolamine ameliorates mitochondrial dysfunction in cardiolipin-deficient yeast cells. J. Biol. Chem. 293, 10870–10883 (2018).
To Academic Professional Track Faculty