Abstract 17142: Parkin Deficiency Shortens Life Span and Accelerates Cardiac Aging: Role of Telomere Dysfunction and Mitochondrial Genome Instability

Abstract

Background: Aging is accompanied with unfavorable geometric and functional changes in the heart involving dysregulated autophagy and mitochondrial integrity. Telomere dysfunction plays a complex role in life span and cardiac aging although the interplay between mitophagy and telomere function remains elusive. Method: This study examined the impact of global Parkin ablation on lifespan and cardiac aging, and the mechanisms involved with a focus on telomere function and mitochondrial integrity. Echocardiography, cardiomyocyte mechanical function, telomerase activity, mitochondrial respiration and mitochondrial genome stability were assessed in young (4-5 months) and old (18 months) WT and Parkin-/- mice. Result: Our results revealed that Parkin ablation shortened lifespan (by 12.4%) and accentuated aging (18 months)-induced unfavorable changes in cardiac function, cardiac remodeling (heart weight, LV wall thickness, LV systolic and diastolic diameters, and cardiomyocyte cross-sectional area) and intracellular Ca 2+ handling. Advanced aging disturbed autophagy, mitophagy and mitochondrial integrity as evidenced by increased p62, decreased levels of beclin-1, Atg7, LC3B, PTEN-induced putative kinase 1 (PINK1), Parkin, UCP-2, PGC-1α and aconitase activity, the effects of which were accentuated by Parkin deficiency. Aging triggered telomerase dysfunction and mitochondrial instability including PGC1α, NRF1, and TFAM, the effect of which was accentuated by Parkin deficiency. Conclusion: Our work revealed that Parkin ablation exacerbates aging-induced cardiac dysfunction and mitochondrial injury, possibly in association with telomere dysfunction and mitochondrial instability.