Genetic sensitivity to mitochondrial toxicity

Duke University, Durham NC

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Genetic variation within the human population can alter sensitivity to various toxicants, including some that target the mitochondria. In fact, cases of exquisite genetic sensitivity to mitochondrial toxicity have been observed with a number of drugs. Many environmental pollutants are also mitochondrial toxicants, or mitotoxicants; however, whether these toxicants pose an increased risk to individuals suffering from mitochondrial disease is unknown. The objective of this proposal is to test mitotoxicants for exacerbation of mitochondrial dysfunction in the context of mitochondrial deficiencies that cause human disease. Taking advantage of highly conserved mitochondrial biology and powerful genetic tools offered by the nematode Caenorhabditis elegans, we will test the hypothesis that deficiency in mitochondrial DNA content or homeostasis processes (i.e. fission, fusion, and mitophagy) exacerbates the mitochondrial toxicity of environmental pollutants, including benzo(a)pyrene, aflatoxin B1, rotenone, and arsenite. Additionally, this research will elucidate changes in mitochondrial energy metabolism that underlie observed gene-environment interactions and then test the functional relevance of these changes at the organismal level. This is important because it will provide insight into how individuals suffering from mitochondrial disease might respond to mitotoxicant exposure. This research aims to help fill a knowledge gap that may leave an already affected population at a higher risk to certain environmental exposures. This is of great societal impact because 1 in 4,000 individuals suffer from mitochondrial disease.