Loss of PINK 1 Increases the Heart ’ s Vulnerability to Ischemia-Reperfusion Injury

Objectives: Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson’s disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction. Methods and Results: Over-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.265.2% PINK1 versus 49.062.4% control; N = 320 cells/group P,0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P,0.05). Hearts excised from PINK1+/+, PINK1+/2 and PINK12/2 mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK12/2 hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/2 hearts (25.162.0% PINK1+/+, 38.963.4% PINK1+/2 versus 51.564.3% PINK12/2 hearts; N.5 animals/group; P,0.05). Cardiomyocytes isolated from PINK12/2 hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1. Conclusions: We show that the loss of PINK1 increases the heart’s vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection. Citation: Siddall HK, Yellon DM, Ong S-B, Mukherjee UA, Burke N, et al. (2013) Loss of PINK1 Increases the Heart’s Vulnerability to Ischemia-Reperfusion Injury. PLoS ONE 8(4): e62400. doi:10.1371/journal.pone.0062400 Editor: Rakesh Kukreja, Virginia Commonwealth University Medical Center, United States of America Received September 28, 2012; Accepted March 21, 2013; Published April 29, 2013 Copyright: 2013 Siddall et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the British Heart Foundation grant number FS/06/023 and supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: d.hausenloy@ucl.ac.uk