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MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70.

ABSTRACT: Mitochondrial Ca2+ overload is a main contributor to mitochondrial damage hence cardiomyocyte death in myocardial ischemia/reperfusion (MI/R) injury. MICU1 has been recently identified as an important regulator of mitochondrial Ca2+ homeostasis. Here we try to identify the role of MICU1 in MI/R, and to investigate whether the mitochondrial importer receptor Tom70 possesses critical roles in the mitochondrial translocation of MICU1 and MI/R. Specific small interfering RNA (20??g) against MICU1 and Tom70, and lentivirus vectors carrying the Tom70a sequences (3.3 × 107?TU) were delivered through intramyocardial injection. Seventy-two hours after injection, mice were subjected to 30?min of MI followed by 3?h (for cell apoptosis and mitochondrial damage assessment) or 24?h (for cardiac function and infarct size determination) of reperfusion. MI/R had no significant effect on total MICU1 expression, but caused significant reduction of MICU1 in mitochondria. Knockdown of MICU1 significantly aggravated MI/R injury, as evidenced by enlarged infarct size, depressed cardiac function and increased myocardial apoptosis. Moreover, MICU1 deficiency resulted in markedly aggravated mitochondrial Ca2+ overload, consequently destructed mitochondrial morphology and suppressed mitochondrial function (evidenced by decreased ATP production). Interestingly, mitochondrial Tom70 was also decreased in MI/R. Genetic loss-function study revealed that mitochondrial MICU1 expression was depressed by Tom70 ablation. Furthermore, Tom70 deficiency significantly aggravated MI/R injury and worsened mitochondrial Ca2+ overload. However, supplementation of Tom70 significantly attenuated MI/R injury, preserved mitochondrial morphology and function, and inhibited mitochondrial Ca2+ overload, all of which were abolished by MICU1 suppression. Mitochondrial Tom70/MICU1 pathway protects against MI/R injury, in which mitochondrial localization of MICU1 is governed by Tom70, and MICU1 serves as an indispensable factor in Tom70's cardioprotection.

SUBMITTER: Xue Q

PROVIDER: S-EPMC5550843 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70.

Xue Qiang Q Pei Haifeng H Liu Qinshe Q Zhao Mingjun M Sun Jing J Gao Erhe E Ma Xinliang X Tao Ling L

Cell death & disease 20170713 7

Mitochondrial Ca<sup>2+</sup> overload is a main contributor to mitochondrial damage hence cardiomyocyte death in myocardial ischemia/reperfusion (MI/R) injury. MICU1 has been recently identified as an important regulator of mitochondrial Ca<sup>2+</sup> homeostasis. Here we try to identify the role of MICU1 in MI/R, and to investigate whether the mitochondrial importer receptor Tom70 possesses critical roles in the mitochondrial translocation of MICU1 and MI/R. Specific small interfering RNA (2 ...[more]

PMID: 28703803

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Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

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MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70.

Publications

MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70.

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