Mitochondrial Quality Control in the Aging Myocardium

University Of California, San Diego, La Jolla CA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Cardiovascular disease remains a significant health risk for the elderly and aging itself significantly increases cardiovascular morbidity. Therefore, better understanding of the pathophysiological mechanisms underlying aging is critical. Accumulation of dysfunctional mitochondria in cells has been implicated as a cause of the aging process and a number of age-related pathologies but why these mitochondria accumulate in aging cells is currently unclear. In the heart, the primary function of mitochondria is to meet the high energy demand of the beating myocytes by providing ATP through oxidative phosphorylation. However, mitochondria can quickly change into death-promoting organelles. They can become excessive producers of reactive oxygen species and release pro-death proteins. Not surprisingly, cells have developed a defense mechanism against aberrant mitochondria that can cause harm to the cell. Studies have found that dysfunctional mitochondria are rapidly sequestered by autophagosomes and subsequently delivered to lysosomes for degradation. Recent studies have demonstrated that the E3 ubiquitin ligase Parkin plays an important role in marking dysfunctional mitochondria for degradation in cells. Parkin ubiquitinates proteins in the outer membrane which serves as labels for the autophagosomes to engulf them. Although studies have reported that Parkin plays an important role in adapting to acute stress, no studies to date have focused on Parkin's role in aging myocytes. In this exploratory proposal, we will investigate the hypothesis that Parkin-mediated mitophagy plays an important role in preventing development of age-related cardiomyopathy. Unfortunately, mitochondrial clearance is decreased with age which leads to accumulation of dysfunctional mitochondria. We hypothesize that the reduced mitochondrial clearance in the aged myocardium is caused by oxidative modification and inactivation of Parkin. These hypotheses will be tested with two aims. Aim 1 will explore the importance of Parkin-mediated mitochondrial clearance in preventing age-related cardiomyopathy. Using a mouse model carrying a proofreading defective mitochondrial DNA polymerase ?POLGm/m), we will investigate the importance of Parkin in clearing mitochondria with accumulating mtDNA mutations in vitro and in vivo. We have also crossed the POLGm/m mice with Parkin deficient mice and cardiac specific Parkin transgenic mice to explore the effect on mitochondrial clearance and age-related cardiomyopathy. In aim 2, we will investigate whether increased oxidative stress in the aging myocardium contributes to misfolding and inactivation of Parkin. These studies will provide important novel insight into the role of Parkin-mediated mitophagy in preventing age-related cardiomyopathy.