Abstract
Myocyte function and survival relies on the maintenance of a healthy population of mitochondria. The PINK1/Parkin pathway plays an important role in clearing defective mitochondria via autophagy in cells. However, how the PINK1/Parkin pathway regulates mitochondrial quality control and whether it coordinates with other mitophagy pathways are still unclear. Therefore, the objective of this study was to investigate the effect of PINK1-deficiency on mitochondrial quality control in myocytes. Using PINK1-deficient (PINK1-/-) mice, we found that Parkin is recruited to damaged cardiac mitochondria in hearts after treatment with the mitochondrial uncoupler FCCP or after a myocardial infarction even in the absence of PINK1. Parkin recruitment to depolarized mitochondria correlates with increased ubiquitination of mitochondrial proteins and activation of mitophagy in PINK1-/- myocytes. In addition, induction of mitophagy by the atypical BH3-only protein BNIP3 is unaffected by lack of PINK1. Overall, these data suggest that Parkin recruitment to depolarized cardiac mitochondria and subsequent activation of mitophagy is independent of PINK1. Moreover, alternative mechanisms of Parkin activation and pathways of mitophagy remain functional in PINK1-/- myocytes and could compensate for the PINK1 deficiency.
Highlights
Mitochondria play a critical role in myocytes by providing them with ATP via oxidative phosphorylation
We found that Parkin levels rapidly increased in the mitochondrial fraction in both WT and PINK1-/- hearts after perfusion with FCCP (Fig 1A), suggesting that PINK1 is not required for the recruitment of Parkin to depolarized cardiac mitochondria
Studies have suggested that the accumulation of PINK1 triggers recruitment of Parkin to mitochondria [6, 28, 29], but we found that perfusion of WT hearts with FCCP for 5 or 15 min did not result in accumulation of endogenous PINK1 at the mitochondria (Fig 1B)
Summary
Mitochondria play a critical role in myocytes by providing them with ATP via oxidative phosphorylation. Mitochondria are important for other critical cellular processes including the sequestration of excess cytosolic calcium [1]. Myocyte function and survival depends on the maintenance of a healthy population of mitochondria. A mitochondrion that is dysfunctional or damaged produces less ATP, but can produce excess reactive oxygen species (ROS) and release proteins that activate cell death pathways [2]. Cells have mitochondrial quality control mechanisms in place to ensure a quick response to damage resulting from changes in the cellular environment. Protein-level quality control includes the removal of dysfunctional proteins by mitochondrial proteases [3] or through segregation into
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