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Loss of PINK1 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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639249/ https://www.ncbi.nlm.nih.gov/pubmed/23638067 http://dx.doi.org/10.1371/journal.pone.0062400 |
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author | Siddall, Hilary K. Yellon, Derek M. Ong, Sang-Bing Mukherjee, Uma A. Burke, Niall Hall, Andrew R. Angelova, Plamena R. Ludtmann, Marthe H. R. Deas, Emma Davidson, Sean M. Mocanu, Mihaela M. Hausenloy, Derek J. |
author_facet | Siddall, Hilary K. Yellon, Derek M. Ong, Sang-Bing Mukherjee, Uma A. Burke, Niall Hall, Andrew R. Angelova, Plamena R. Ludtmann, Marthe H. R. Deas, Emma Davidson, Sean M. Mocanu, Mihaela M. Hausenloy, Derek J. |
author_sort | Siddall, Hilary K. |
collection | PubMed |
description | 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 (29.2±5.2% PINK1 versus 49.0±2.4% 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+/− and PINK1−/− mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1−/− hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/− hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/− versus 51.5±4.3% PINK1−/− hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1−/− 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. |
format | Online Article Text |
id | pubmed-3639249 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36392492013-05-01 Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury Siddall, Hilary K. Yellon, Derek M. Ong, Sang-Bing Mukherjee, Uma A. Burke, Niall Hall, Andrew R. Angelova, Plamena R. Ludtmann, Marthe H. R. Deas, Emma Davidson, Sean M. Mocanu, Mihaela M. Hausenloy, Derek J. PLoS One Research Article 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 (29.2±5.2% PINK1 versus 49.0±2.4% 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+/− and PINK1−/− mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1−/− hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/− hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/− versus 51.5±4.3% PINK1−/− hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1−/− 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. Public Library of Science 2013-04-29 /pmc/articles/PMC3639249/ /pubmed/23638067 http://dx.doi.org/10.1371/journal.pone.0062400 Text en © 2013 Siddall et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Siddall, Hilary K. Yellon, Derek M. Ong, Sang-Bing Mukherjee, Uma A. Burke, Niall Hall, Andrew R. Angelova, Plamena R. Ludtmann, Marthe H. R. Deas, Emma Davidson, Sean M. Mocanu, Mihaela M. Hausenloy, Derek J. Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury |
title | Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury |
title_full | Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury |
title_fullStr | Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury |
title_full_unstemmed | Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury |
title_short | Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury |
title_sort | loss of pink1 increases the heart's vulnerability to ischemia-reperfusion injury |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639249/ https://www.ncbi.nlm.nih.gov/pubmed/23638067 http://dx.doi.org/10.1371/journal.pone.0062400 |
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