Understanding environmental mitochondrial health

About This Grant

Mitochondrial function is fundamental to health, as soberingly demonstrated by the wide range of debilitating pathologies and diseases faced by patients with genetically-based mitochondrial deficiencies. Chemical exposure can directly affect mitochondrial function in many different ways, and can also dramatically exacerbate underlying genetic conditions. Because mitochondrial toxicants are common among pollutants, understanding the detailed mechanisms by which these chemicals affect mitochondria, and their interactions with genetic differences, is a highly significant environmental health problem. Unfortunately, the molecular and cellular impacts of different, specific mechanisms of mitochondrial toxicity are poorly understood, and the interactions of such exposures with genetic deficiencies are even more obscure. These knowledge gaps hinder testing, regulatory, and personalized medicine efforts. We seek to understand 1) the biological pathways that respond to mitochondrial DNA damage, especially irreparable mitochondrial DNA damage; 2) the molecular and cellular consequences of different, specific kinds of stressor-mediated changes to mitochondrial integrity and function; 3) how the effects of mitochondrial toxicants change in the context of human mitochondrial disease genes. To address these knowledge gaps, we are employing a translational approach integrating a powerful mechanistic in vivo laboratory model, Caenorhabditis elegans, with cell culture experiments including cells from mitochondrial disease patients. We will continue to define the molecular and cellular outcomes of different kinds of mitochondrial toxicity, and to identify novel biological pathways that defend mitochondria and the mitochondrial genome. We will test how deficiencies in these genes, and genes known to cause mitochondrial disease, alter sensitivity to mitochondrial toxicants, in both C. elegans and patient-derived cells. We are developing powerful transgenic tools that allow us to measure key aspects of mitocondrial function and dysfunction, including energetics, morphology, and alterations to redox tone, in a cell-specific fashion and in vivo, in C. elegans. We are deriving iPSCs and differentiated, mitochondrial disease-relevant cells for testing gene-environment interactions. Given the prevalence of both mitochondrial gene variability and mitotoxicant exposure, understanding the detailed mechanisms by which mitotoxicants act, the impacts of the genetic deficiencies, and their interactive effects will be impactful for many people. Addressing these scientific challenges will be transformative for human health by providing mechanistic knowledge critical to understanding cellular and higher-level effects of mitochondrial toxicity, informing treatment and personalized intervention options, and developing appropriate testing and regulatory strategies.