Elucidating mechanisms of mitochondrial DNA copy number regulation in aging - PROJECT SUMMARY/ABSTRACT An aging human population has revealed the burden of chronic illness and age-related diseases. By understanding the cellular and molecular drivers of aging, we will be better equipped to develop therapeutics that delay age-related diseases. Mitochondrial dysfunction is a cellular driver of aging, yet strategies to therapeutically target mitochondrial dysfunction are lacking. It is well established that the accumulation of mutations in mitochondrial DNA (mtDNA) contributes to mitochondrial dysfunction in aging. Recent work has demonstrated that increased absolute levels of wild-type mtDNA can compensate for the effects of pathogenic mtDNA mutations and promote mitochondrial function. Thus, a therapeutic strategy to target mitochondrial dysfunction in aging is to elevate mtDNA copy number. However, the molecular regulators of mtDNA copy number are poorly defined. Moreover, recent evidence suggests that mtDNA copy number declines with age and, in addition to the accumulation of mtDNA mutations, may directly contribute to aging. To establish mtDNA as a therapeutic target in aging, we need to better characterize the mechanisms of mtDNA copy number regulation and to determine the direct impact of altered mtDNA copy number on aging phenotypes. In this proposal, I have discovered that C. elegans experience a significant age-dependent loss of mtDNA. Surprisingly, this loss of mtDNA is not associated with a decline in mitochondrial organellar content, suggesting that there is a sub-organellar mechanism selectively driving the loss of mtDNA. Additionally, I have found that this loss of mtDNA is suspended during an alternative developmental stage of C. elegans called dauer. My preliminary data demonstrates that reduced signaling drives mtDNA maintenance during the dauer state. Thus, I hypothesize that a sub-organellar mechanism eliminates mtDNA in C. elegans with age (Aim 1), that pathways downstream of reduced insulin signaling drive mtDNA maintenance during dauer (Aim 2), and that mtDNA depletion impairs mitochondrial function and causes aging phenotypes (Aim 3). This work will be conducted at Vanderbilt University under the supervision of Dr. Maulik Patel, PhD, Assistant Professor of Biological Sciences, who has made fundamental discoveries regarding mtDNA regulation and inheritance. Additional support will be provided by Dr. Patrick Hu, MD, PhD, a practicing physician-scientist and C. elegans geneticist who studies fundamental mechanisms that govern development and aging, including dauer formation. I will receive feedback from a strong advisory committee with experience in mitochondrial biology, genetics, and aging physiology. Successful completion of this project will advance our understanding of fundamental mechanisms of mitochondrial DNA regulation and establish therapeutic targets for preserving mtDNA copy number.
