Urinary Biomarkers of Renal Mitochondrial Dysfunction

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify and validate biomarkers of mitochondrial dysfunction due to environmental stressors. Diverse acute insults from surgery, trauma, ischemia/reperfusion (I/R) and drug andenvironmental chemical toxicity lead to mitochondrial dysfunction and result in cell injury and death in many organs/tissues (e.g. heart, lung, brain, liver and kidney). Furthermore, mitochondrial dysfunction can contribute to cell injury through increasedproduction of reactive oxygen and nitrogen species. Mitochondrial dysfunction is also a component of many chronic diseases such as metabolic syndrome, diabetes, neurodegenerative diseases, and aging. Consequently, there is a great need for non-invasive biomarkers of mitochondrial dysfunction. We hypothesize that urinary mitochondrial DNA (mtDNA) and urinary protein levels of mitochondrial ATP synthase (ATPS) subunits are sensitive and specific markers of mitochondrial dysfunction in acute kidney injury (AKI). Our preliminary studies support this hypothesis by demonstrating increased urinary mtDNA and ATPS in mice subjected to I/R induced AKI when renal mitochondrial dysfunction was present. These preliminary studies provide strong evidence in support of ourhypothesis. The following Specific Aims will be examined: 1) Using a mouse model with different degrees of I/R induced AKI, elucidate urinary changes in mtDNA, mitochondrial ATPS subunits and other mitochondrial proteins; integrate these changes with renal mitochondrial dysfunction over time; and compare and contrast the changes in these endpoints with general urinary AKI biomarkers. These studies will result in new urinary markers of mitochondrial dysfunction in animals. Comparison of mitochondrial DNA, protein and function over a range of times and grades of injury will permit better understanding of the timing and mechanisms of injury and recovery. Finally, these biomarkers can be tested in humans and translated into laboratory and clinical practice.PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Diverse acute insults such as surgery, trauma, ischemia/reperfusion and drug and environmental chemical toxicity lead to mitochondrial dysfunction and result in cell injury and death in the kidney. However, there are no non-invasive biomarkers of renal mitochondrial dysfunction. The proposed studies will identify and validate new urinary biomarkers of renal mitochondrial dysfunction.