Mitochondria are central regulators of cellular bioenergetics. Reflecting the critical role for mitochondria in metabolism, energy production, and production of reactive oxygen species, a wide range of human diseases have been linked to mitochondrial dysfunction. Included in these, genetic oxidative phosphorylation disorders represent the most common group of inborn errors of metabolism. Isolated complex I deficiency is the most frequent inherited oxidative phosphorylation disorder and leads to a variety of severe metabolic diseases. Patients with complex I deficiency have a range of clinical presentations that reflect particularly involvement of the brain, heart and skeletal muscle. Leigh's disease, a fatal encephalomyopathy, is the most common clinical syndrome. Isolated complex I deficiency usually leads to death within the first two years of life and there is no effective treatment. Although a substantial amount is know regarding the structure and biochemical function of complex I, the mechanisms leading to cellular dysfunction and death in diseases associated with complex I deficiency are much less well understood. A paucity of animal models has contributed to the slow progress in understanding the pathogenesis of complex I deficiency. To address these issues and allow for a detailed genetic analysis of complex I deficiency, we have modeled the disorder in the simple genetic model organism Drosophila. Results of preliminary genetic modifier analyses lead us to propose a novel hypothesis to explain complex I pathogenesis: accumulation of excess reducing equivalents leading to reductive stress. We will now test the role of reductive stress in complex I deficiency using a combination of genetics and biochemistry. We will first perform a genetic dissection of the enzymatic pathways leading to the production and metabolism of NADH, a critical substrate of complex I. We will then use biochemical assays to measure directly the levels of reductive equivalents in animals with altered complex I function, and in our complex I model in the context of genetically modified backgrounds. If successful, our studies will validate a novel hypothesis regarding the pathogenesis of complex I deficiency and thus set the stage for development of new therapeutic approaches.

Public Health Relevance

Complex I deficiency is a devastating disorder that causes severe disability and early death in affected children. We will use a fast, inexpensive in vivo model system to identify pathways that mediate neuronal death and dysfunction in this disease. Results from our system will provide important implications for therapy development and may also help us understand how more common brain disorders, like Parkinson's disease, occur and progress.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Gwinn, Katrina
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Brigham and Women's Hospital
United States
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Hegde, Vijay R; Vogel, Rutger; Feany, Mel B (2014) Glia are critical for the neuropathology of complex I deficiency in Drosophila. Hum Mol Genet 23:4686-92