Abstract 149: Parkin Translocation And Mitophagy Occur Independently of PINK1 in the Myocardium

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We recently reported that Parkin plays a crucial role in preserving myocardial tissue following a myocardial infarction (MI) by promoting removal of damaged mitochondria via autophagy (mitophagy). Parkin is thought to function downstream of the serine/threonine kinase PINK1 for mitophagy of mitochondria that have lost membrane potential (ΔΨm). Here, we describe the ability of Parkin to translocate to dysfunctional mitochondria in the absence of PINK1. We discovered that after 4 hours of MI, Parkin accumulated on mitochondria in the infarct border zone in both wild type (WT) and PINK1 knockout mice (PINK1-/-). Additionally, ex vivo perfusion of PINK1-/- hearts with the mitochondrial uncoupler FCCP caused rapid translocation of Parkin to mitochondria, equivalent to the response in WT hearts. We further confirmed Parkin translocation and subsequent mitophagy by fluorescence microscopy in isolated PINK1-/- adult cardiac myocytes treated with the mitochondrial complex I inhibitor rotenone. Rotenone-stimulated Parkin translocation resulted in increased co-localization of GFP-LC3-labeled autophagosomes with mitochondria in both WT and PINK1-/- myocytes. Thus, PINK1 is dispensable for Parkin translocation and mitophagy in cardiac myocytes. In contrast, we found that Drp1-mediated mitochondrial fission was a prerequisite for Parkin translocation and mitophagy activation. Drp1 translocation to mitochondria preceded Parkin translocation in WT and PINK1-/- hearts perfused with FCCP. Moreover, overexpression of the dominant negative Drp1-K38E mutant prevented Parkin translocation in rotenone-treated isolated adult rat cardiac myocytes. Interestingly, while Drp1 was able to rapidly translocate to mitochondria in FCCP-perfused Parkin-/- hearts, Drp1 translocation to border zone mitochondria was only observed in WT hearts after MI and not Parkin-/-. This suggests that Parkin stabilizes Drp1 that has translocated to mitochondria upon damage. We conclude that while Parkin translocation to cardiac mitochondria is independent of PINK1 activity, Drp1-mediated fission is required for Parkin translocation. Parkin and PINK1 are therefore components of distinct but overlapping pathways for mitochondrial maintenance in the heart.

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