miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury

Abstract

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Emerging evidences suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction (MI) and heart failure. However, the molecular components regulating mitochondrial network in the heart remain largely unidentified. Here we report that miR-361 and prohibitin 1 (PHB1) constitute an axis that regulates mitochondrial fission and apoptosis. The results show that PHB1 attenuates mitochondrial fission and apoptosis in response to hydrogen peroxide treatment in cardiomyocytes. Cardiac-specific PHB1 transgenic mice show reduced mitochondrial fission and myocardial infarction sizes after myocardial infarction surgery. MiR-361 is responsible for the dysfunction of PHB1 and suppresses the translation of PHB1. Knockdown of miR-361 reduces mitochondrial fission and apoptosis in vivo and in vitro. MiR-361 cardiac-specific transgenic mice represent elevated mitochondrial fission and myocardial infarction sizes upon myocardial ischemia injury. This study identifies a novel signaling pathway composed of miR-361 and PHB1 that regulates mitochondrial fission program and apoptosis. This discovery will shed new light on the therapy of myocardial infarction and heart failure. The heart drives the blood flow in the body and it has a large requirement of energy. Mitochondria meet the high energy demand of the heart by consistently providing large amounts of ATP through oxidative phosphorylation. Thus, mitochondrial malfunction is tightly related to cardiac diseases and contributes to cardiomyocyte injury, cardiomyopathy and heart failure. Mitochondria morphology is also associated with the function. Mitochondria constantly undergo fission and fusion. Fission leads to the formation of small round mitochondria and promotes cell apoptosis, 1-7 whereas fusion results in mitochondria elongation and have a protective role in cardiomyocytes maintenance. 8 The above findings strongly suggest that mitochondrial fission and fusion machinery is important for cardiac function. In addition, unveiling the mechanism of mitochondrial network regulation will provide a novel therapeutic strategy for heart failure.The mitochondrial prohibitin complex is a macromolecular structure at the inner mitochondrial membrane that is composed of prohibitin 1 (PHB1) and prohibitin 2 subunits. 9These two proteins comprise an evolutionary conserved and ubiquitously expressed family of membrane proteins and are implicated in several important cellular processes such as mitochondrial biogenesis and function, cell proliferation, replicative senescence, and cell death.10,11 The first mammalian PHB1 was identified as a potential tumor suppressor with anti-proliferative activity.12 Recent findings suggest that PHB1 has an important role in regulating mitochondrial morphology.Loss of PHB1 results in accumulation of fragmented mitochondria in MEFs and HeLa cells.13,14 However, it is not yet clear whether PHB1 participates in ...

Roles of mitochondrial dynamics modulators in cardiac ischaemia/reperfusion injury

“…Cardiac dysfunction in I/R injury is associated with an imbalance of mitochondrial dynamics. Numerous studies have shown that during the reperfusion period mitochondria undergo fission and that there is an absence or reduction in mitochondrial fusion . Mitochondria fission results in a higher susceptibility to mitochondrial permeability transition pore (mPTP) opening, leading to an activation of the apoptotic pathway by the release of caspase family proteins resulting in cell death at the time of myocardial reperfusion .…”

“…The timing of the administration of treatment is an essential determinant of its therapeutic efficacy against I/R injury. Several studies using pharmacological and non‐pharmacological interventions to inhibit mitochondrial fission found that the greatest efficacy was ensured if treatment was given prior to ischaemia . Mitochondrial fission inhibitors given before the induction of ischaemia led to improved cardiac cell survival and reduced myocardial infarct size.…”

Effects of miRNAs on myocardial apoptosis by modulating mitochondria related proteins

“…In addition to mitochondrial dynamic directly related proteins, prohibitin 1 (PHB1), an inner mitochondrial membrane protein, also participates in the regulation of mitochondrial morphological change and it attenuates mitochondrial fission in cardiomyocytes. In infarcted heart, PHB1 is downregulated by miR‐361, while antagonizing miR‐361 can inhibit mitochondrial fission, apoptosis and infarct sizes . The E2F1 is a key transcription factor in cell cycle of cardiomyocytes, which can induce mitochondrial fragmentation and apoptosis in cardiomyocytes through miR‐421 induced suppression of PTEN‐induced putative kinase 1(Pink1), a mitochondrial Ser/Thr kinase involved in protection against mitochondrial dysfunction .…”

“…In addition to mitochondrial dynamic directly related proteins, prohibitin 1 (PHB1), an inner mitochondrial membrane protein, also participatesintheregulationofmitochondrialmorphologicalchange anditattenuatesmitochondrialfissionincardiomyocytes.Ininfarcted heart, PHB1 is downregulated by miR-361, while antagonizing miR-361 can inhibit mitochondrial fission, apoptosis and infarct sizes. 38 TheE2F1isakeytranscriptionfactorincellcycleofcardiomyocytes, 51 This indicates that narrowed perspective shouldbelimitedwhileinvestigatingdiverseroleofmiRNAs.…”

Mitochondrial Dynamics and Heart Failure

“…OPA1 has a role in protecting cells from apoptosis, at least in part by preventing cytochrome c release from the cristae into the cytosol (32;137). Prohibitins also have a role in regulating cristae structure and OPA1 localization, and thus are indirectly anti-apoptotic (126;142;195). …”