NDUFA4L2 protects against ischaemia/reperfusion‐induced cardiomyocyte apoptosis and mitochondrial dysfunction by inhibiting complex I

Abstract

Myocardial ischaemia/reperfusion (I/R) injury may cause the apoptosis of cardiomyocytes as well as mitochondrial dysfunction. The aims of the present study were to investigate whether NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) on myocardial ischaemia-reperfusion (I/R) injury and the underlying molecular mechanism. The hypoxia-reperfusion (H/R) model was established in vitro using H9c2 cells to simulate I/R injury. NDUFA4L2 and complex I expression levels were detected using RT-PCR and western blot. The apoptosis of H9c2 cells was evaluated by flow cytometry and the expression of Bax and Bcl-2 was detected by western blot. The mitochondrial function was assessed by ATP concentration, mPTP opening and cytochrome c (cyto C) expression. Our data indicated that NDUFA4L2 expression was significantly down-regulated in myocardial H/R injury. Overexpression of NDUFA4L2 led to a dramatic prevention of H/R-induced apoptosis accompanied by a decrease in the expression of Bax and an increase in the expression of Bcl-2. Meanwhile, augmentation of NDUFA4L2 dramatically prevented mitochondrial dysfunction caused by H/R as reflecting in the increased ATP concentration, delayed mPTP opening, as well as down-regulated cyto C expression. Moreover, complex I activation was heightened and negatively regulated by NDUFA4L2. Silencing complex I conspicuously attenuated cell apoptosis and mitochondrial dysfunction. Taken together, our findings demonstrated that NDUFA4L2 protects against H/R injury by preventing myocardium apoptosis and mitochondrial dysfunction via the complex I, and may be a potential therapeutic approach for attenuating myocardial I/R injury.

Label-free quantitative SWATH-MS proteomic analysis of adult myocardial slices in vitro after biomimetic electromechanical stimulation

“…Many enzymes that are involved in a respiratory chain like NADH dehydrogenases (Ndufa6, Ndufa3, Ndufa2, Ndufa13), cytochrome c oxidase subunit 7B (Cox7b) or cytochrome b-c1 complex subunit (Uqcrfs1) were up in the proteomic analysis when 2.2 was compared to the C group. For example, inhibiting complex I NDUFA4L2 was found to protect against mitochondrial dysfunction and ischemia/reperfusion‐induced cardiomyocyte apoptosis 25 . Interestingly, mitochondrial superoxide dismutase (Sod2), which destroys superoxide anion radicals normally produced within the cells, was found in 2.2 heart slices 26 .…”

LRRFIP2 modulates the response to hypoxia during embryonic cardiogenesis

“…It will be important to determine the number of Caspase3 + mutant CM at E11.5 to test this hypothesis. While many genes implicated in the oxidative phosphorylation pathway are down-regulated in mutant CM, Ndufa4l2 known to inhibit the complex I of the respiratory chain (Li et al, 2017) is overexpressed. NDUFA4L2 accumulated in all myocardium of Lrrfip2 -/- embryos at E10.5 and may participate to the lower ROS level observed in mutant embryos as a consequence of decreased complex I activity.…”

Identification of mitochondrial function‐associated lncRNAs in septic mice myocardium

“…Decreased ATP production, oxidative stress, and abnormal morphology of mitochondria are the typical characteristics of mitochondrial damage in septic cardiopathy. ATP production is controlled by the mitochondrial electron transport chain 34 . Ndufa4l2 gene encodes Ndufa4l2 protein which is a subunit of complex I of the electron transport chain.…”