Life requires ATP. As the site of ATP synthesis in eukaryotic cells, mitochondria consume ~98% of the oxygen we breathe each day. Mitochondria have two functionally distinct membranes: the outer membrane forms the barrier between the cytosol and the mitochondrial intermembrane space, the inner membrane is ~70% protein and separates the intermembrane space from the mitochondrial interior (the matrix) where ATP synthesis happens. Both membranes contain a variety of channels and transporters. Aside from bringing cells to life, mitochondria are have central roles in calcium homeostasis, heat generation, and lipid oxidation, and can unleash death by initiating both apoptotic and necrotic cellular death pathway.

Mitochondria are thought to have evolved from ± proteobacteria. As these organelles bridge two kingdoms of life, mitochondrial membrane proteins are ideal candidates for leveraging the success of existing bacterial expression systems as a means to produce proteins for structural work. These proteins will also be instructive to our efforts in the development of systems for the expression of eukaryotic membrane proteins at the Membrane Protein Expression Center (MPEC) at UCSF.

Because of their central place in metabolism, mitochondria are emerging as important players in a wide range of human diseases. Mitochondrial dysfunction is implicated in aging and age related neurodegeneration in Alzheimer's disease and Parkinson's disease, cancer, type 2 diabetes, ischemia and reperfusion injuries in the heart and brain, obesity, and infertility. Our initial target set is central to the molecular events that link mitochondria to these pathologies. Understanding the structures of mitochondrial membrane proteins will have a direct impact on our ability to ask refined questions about the molecular basis of mitochondrial function and will provide invaluable information for the development of small molecules to treat diseases that originate in metabolic disorders of the mitochondria.

[1] Structural understanding of ion channel action and regulation
[2] Molecular evolution of ion channel modulators for channels
[3] Structural understanding of membrane proteins that power the cell through their actions in mitochondria