Edward Mills

Research Interests

In mammals, up to 25% of overall basal metabolic rate is devoted to a futile cycle of proton extrusion from and leak back into the mitochondrial matrix during oxidative phosphorylation. Commonly referred to as bioenergetic "respiratory inefficiency", proton leak uncouples fuel oxidation from ATP synthesis, and is regulated primarily by uncoupling proteins. From a teleological perspective, the evolution of a biological pathway of energy wasting would seem surprising. However, a variety of studies indicate this process is a thermogenic mechanism that mediates adaptive heat production and antagonizes the generation of mitochondrial oxidant species along with the development of age-related disease. Projects in my laboratory incorporate rodent, nematode, cell-based, and biochemical approaches to explore the mechanisms regulating mitochondrial respiratory inefficiency, and the role of this process in normal cell function, metabolic physiology and age-related diseases.

Two broad research questions guide the work in our lab:

1. What are the physiologic functions and mechanisms of regulation / action of uncoupling proteins? These projects use C. elegans and mouse gain and loss of function uncoupling protein mutants, along with cultured cells and in vitro reconstitution systems, to gain insight into the molecular regulation and function of uncoupling proteins in metabolic physiology (substrate transport/oxidation, fat storage) and age related disease (cancer, obesity, diabetes).
2. What are the mechanisms by which mitochondrial energy conversion couples to the regulation of cellular signaling pathways?

Mitochondria are thought to participate in growth control and stress pathways in part by their production of approximately 85% of the cellular reactive oxidant species, including hydrogen peroxide and superoxide. These projects use cell biological and biochemical approaches to identify novel cytoplasmic sensors of mitochondrial oxidants, and to understand the physiologic relevance of these molecular interactions in the integration cellular physiology.

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