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Dennis Winge

Professor of Internal Medicine and of Biochemistry

B.A. Concordia College

Ph.D. Duke University

Research

References

dennis.winge@hsc.utah.edu

Dennis Winge's Lab Page

Dennis Winge's PubMed Literature Search

Research

Defects in the assembly of the mitochondrial OXPHOS respiratory chain contribute to numerous inherited and acquired diseases of patients with cardiomyopathy, hepatopathy, and neurological disorders. We are interested in elucidating the mechanisms of assembly of respiratory complexes II, III and IV in yeast as an experimental system. Many assembly factors are known that mediate assembly of these respiratory complexes and a large fraction of these are conserved in human cells. Thus, functional studies in yeast contribute to our understanding of the assembly processes in humans. We seek to identify new proteins that mediate the biogenesis of the OXPHOS respiratory complexes and elucidate their mechanism of action.

The assembly of cytochrome oxidase (CcO) requires the coordinate assembly of subunits translated in both the cytoplasm and mitochondria as well as the insertion of heme and copper redox cofactors. CcO biogenesis commences with the synthesis of Cox1 followed by formation of the heme a cofactor centers and subsequent addition of other subunits. The Cox1 assembly intermediate is conditionally deleterious in cells stalled in subsequent assembly steps. The high spin heme a3 center in Cox1 can generate reactive oxygen species when the Cox1 intermediate accumulates. To avoid the potential danger of this pro-oxidant intermediate, yeast employ chaperone proteins to guide this assembly intermediate through the Cox1 maturation process and induce a quality control protease to remove any stalled assembly intermediates. We are focused on elucidating the process of redox cofactor insertion as well as the quality control proteolytic system. We seek to identify additional assembly factors in the CcO biogenesis process and elucidate the mechanism of their assembly function. In these studies, we use a combination of in vitro biochemical, in vivo cellular assays and genetic analyses to elucidate the mechanism and pathway by which these assembly proteins mediate CcO formation. Succinate dehydrogenase (Complex II) and cytochrome c reductase (Complex III) also contain a myriad of metal cofactors including FeS and heme centers. We seek to understand the assembly of these centers. We are studying two new Complex III assembly factors that mediate a late step involving the translocation of the folded Rieske Fe/S protein across the inner membrane. Proteins are usually translocated across bilayers as unfolded molelcules. We are trying to elucidate the mechanism by which two novel mitochondrial proteins contribute to the assembly of the multi-subunit succinate dehydrogenase.

A second major focus in the Winge laboratory concerns bioavailable pools of copper and zinc within the mitochondrial matrix used in the metallation of metalloproteins. We are using biophysical techniques to structurally characterize the matrix copper and zinc labile complexes and genetic approaches to identify the key transporters that transport copper and zinc ions into the matrix.

The third focus of the group concerns redox chemistry in the mitochondrial intermembrane space (IMS). This compartment is an unusual cellular compartment in that its redox potential is significantly more oxidizing than the matrix or cytoplasm. We are working to understand how redox control modulates CcO biogenesis.

References