Journal Article

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

Zhao, Mingjun, Pei, Haifeng, Xue, Qiang, Ma, Xinliang, Sun, Jing, Gao, Erhe, Tao, Ling, Liu, Qinshe

2017

Overview

Mitochondrial Ca 2+ 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 2+ 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  μ g) against MICU1 and Tom70, and lentivirus vectors carrying the Tom70a sequences (3.3 × 10 7  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 Ca 2+ 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 Ca 2+ overload. However, supplementation of Tom70 significantly attenuated MI/R injury, preserved mitochondrial morphology and function, and inhibited mitochondrial Ca 2+ 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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/2 / 631/443/592/75/593/15/1939 / 631/45/612/1222 / 631/80/2023/2022 / 631/80/86 / Adenosine triphosphatase / Animals / Antibodies / Apoptosis / Biochemistry / Biomedical and Life Sciences / Calcium (mitochondrial) / Calcium - metabolism / Calcium homeostasis / Calcium-Binding Proteins - antagonists & inhibitors / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cardiomyocytes / Cell Biology / Cell Culture / Death / Disease Models, Animal / Enzyme-Linked Immunosorbent Assay / Heart / Heart diseases / Homeostasis / Immunology / Injection / Ischemia / Life Sciences / Localization / Male / Membrane Potential, Mitochondrial / Mice / Microscopy, Electron, Transmission / Mitochondria / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial Membrane Transport Proteins - antagonists & inhibitors / Mitochondrial Membrane Transport Proteins - genetics / Mitochondrial Membrane Transport Proteins - metabolism / Morphology / Myocardial Infarction - pathology / Myocardial ischemia / Myocardial Reperfusion Injury - metabolism / Myocardial Reperfusion Injury - pathology / Myocardium - metabolism / Original / original-article / Reperfusion / RNA Interference / RNA, Small Interfering - metabolism / siRNA / Supplements / Troponin I - analysis