Metals and Membranes in Mitochondrial Metabolism and Human Disease
The research in my laboratory is focused on the discovery and characterization of genes required for building the mitochondrial energy generating machinery. Our work is motivated by the fact that mutations in these genes result in rare but often fatal mitochondrial disorders for which no therapy exists. We apply the tools of genetics, genomics, and biochemistry in yeast, zebrafish, and mouse models to discover and characterize novel mitochondrial disease-causing genes. We then use our genetic models to perform targeted drug screens to develop therapeutic approaches for these debilitating human disorders. Some of our projects are described below:
Mitochondrial Respiratory Chain Biogenesis
Mitochondrial respiratory chain (MRC) is the primary means by which most eukaryotic organisms generate biological energy. Building the MRC is a complex process that requires hundreds of genes, many of which are yet to be identified. We use an integrative approach based on clues from evolutionary history, human genetics, and nutrient-sensitized screens to systematically discover the “missing” factors in MRC biogenesis. We assign functions to these newly discovered genes by using biochemical, cellular, and molecular techniques. Using this approach, we have discovered proteins required for the delivery of copper to the MRC complex (See Figure 1).
Soma, S., Morgada, M.N., Naik, M.T., Boulet, A., Roesler, A.A., Dziuba, N., Ghosh, A., Yu, Q., Lindahl, P.A., Ames, J.B., Leary, S.C., Vila, A.J., Gohil, V.M. COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase. Cell Reports. 29:4114-4126.e5 (2019).
Ghosh, A., Pratt, A.T., Soma, S., Theriault, S.G., Griffin, A.T., Trivedi, P.P., Gohil, V.M. Mitochondrial disease genes COA6, COX6B and SCO2 have overlapping roles in COX2biogenesis. Hum. Mol. Genet. 25: 660-671 (2016).
Therapeutic Approaches for Mitochondrial Disorders
To determine the physiological functions of our newly discovered mitochondrial disease genes, we construct yeast, zebrafish, and human cellular models by using gene-editing technologies. By characterizing these models, we have elucidated the role of copper in MRC biogenesis, organismal development, and human disease pathogenesis. We use our genetic models to screen for therapeutic lead molecules and have recently identified elesclomol, a copper ionophore, as a promising drug candidate for the treatment of disorders of copper metabolism including the Menkes disease and a subset of mitochondrial disorders (See Figure 2).
Guthrie, L.M., Soma, S., Yuan, S., Silva, A., Zulkifli, M., Snavely, T.C., Greene, H.F., Nunez, E., Lynch, B., De Ville, C., Shanbhag, V., Lopez, F.R., Acharya, A., Petris, M.J., Kim, B.E., Gohil, V.M., Sacchettini, J.C. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice. Science. 368:620-625 (2020).
Soma, S., Latimer, A.J., Chun, H., Vicary, A.C., Timbalia, S.A., Boulet, A., Rahn, J.J., Chan, S.S.L., Leary, S.C., Kim, B.E., Gitlin, J.D., Gohil, V.M. Elesclomol restores mitochondrial function in genetic models of copper deficiency. PNAS. 115:8161-8166 (2018).
Phospholipid Requirements for Mitochondrial Respiratory Chain Function
The unique phospholipid milieu of the mitochondrial membrane could also influence the assembly and activity of the MRC complexes. We have constructed yeast mutants with defined perturbations in mitochondrial phospholipid composition to systematically determine the role of the three major mitochondrial phospholipids – phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) – in MRC assembly and
activity. Using these mutants, we demonstrated specific requirements of non-bilayer phospholipids, PE and CL, in MRC function. We have also used these mutants to uncover a specific requirement of CL for the human mitochondrial calcium channel. Our work has uncovered the biochemical underpinnings of the pathology associated with Barth syndrome, a rare mitochondrial disorder of CL metabolism (See Figure 3).
Ghosh, S., Ball, W.B., Madaris, T.R., Srikantan, S., Madesh, M., Mootha, V.K., Gohil, V.M. An essential role for cardiolipin in the stability and function of the mitochondrial calcium uniporter. PNAS. 117:16383-16390 (2020).
Baker, C.D., Ball, W.B., Pryce, E.N., Gohil, V.M. Specific requirements of non-bilayer phospholipids in mitochondrial respiratory chain function and formation. Mol. Biol. Cell. 27:2161-171 (2016).