RETRACTED ARTICLE: NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α

Abstract

Mitochondrial fission and mitophagy are considered key processes involved in the pathogenesis of cardiac microvascular ischemia reperfusion (IR) injury although the upstream regulatory mechanism for fission and mitophagy still remains unclear. Herein, we reported that NR4A1 was significantly upregulated following cardiac microvascular IR injury, and its level was positively correlated with microvascular collapse, endothelial cellular apoptosis and mitochondrial damage. However, NR4A1-knockout mice exhibited resistance against the acute microvascular injury and mitochondrial dysfunction compared with the wild-type mice. Functional studies illustrated that IR injury increased NR4A1 expression, which activated serine/threonine kinase casein kinase2 α (CK2α). CK2α promoted phosphorylation of mitochondrial fission factor (Mff) and FUN14 domain-containing 1 (FUNDC1). Phosphorylated activation of Mff enhanced the cytoplasmic translocation of Drp1 to the mitochondria, leading to fatal mitochondrial fission. Excessive fission disrupted mitochondrial function and structure, ultimately triggering mitochondrial apoptosis. In addition, phosphorylated inactivation of FUNDC1 failed to launch the protective mitophagy process, resulting in the accumulation of damaged mitochondria and endothelial apoptosis. By facilitating Mff-mediated mitochondrial fission and FUNDC1-required mitophagy, NR4A1 disturbed mitochondrial homeostasis, enhanced endothelial apoptosis and provoked microvascular dysfunction. In summary, our data illustrated that NR4A1 serves as a novel culprit factor in cardiac microvascular IR injury that operates through synchronous elevation of fission and suppression of mitophagy. Novel therapeutic strategies targeting the balance among NR4A1, fission and mitophagy might provide survival advantage to microvasculature following IR stress.

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

“…These conclusions identify mitochondrial fragmentation as the upstream mediator and trigger event for mitochondrial damage. Our finding is similar to previous studies showing that mitochondrial fragmentation is the pathogenesis for fatty liver [59], gastric cancer [60], cardiac ischaemia-reperfusion injury [15] and diabetic cardiomyopathy [12]. Finally, we found that mitochondrial fragmentation could be repressed by MKP1 via inhibiting the JNK-CaMKII-Fis1 pathway.…”

“…Moderate mitochondrial division helps mitochondria to remove the damaged parts and ensure the homeostasis of the mitochondrial network [13]. However, uncontrolled mitochondrial division, as evidenced by extensively fragmented mitochondria, represses the ability of mitochondria to produce sufficient ATP and finally contribute to the opening of the mitochondrial apoptotic pathway [14,15]. Although mitochondrial fragmentation is observed in hyperglycaemia-challenged cardiomyocytes [12], the role of mitochondrial fragmentation is not defined in diabetic renal damage.…”

“…This finding confirmed that mitochondrial fragmentation was triggered by hyperglycaemia and was inhibited by MKP1 overexpression. Mitochondrial fragmentation is the consequence of excessive mitochondrial fission and/or impaired mitochondrial fusion [15,19]. Western blotting analysis demonstrated that mitochondrial fission-related proteins such as Drp1 and Fis1 were significantly upregulated in hyperglycaemia-treated cells (Fig.…”

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

“…Mitophagy is the result of fusion between mitochondria and lysosome. The green mitochondria locate with red lysosome would generate the orange mitophagy [43]. Then, the number of orange dot was measured to quantify the number of mitophagy.…”

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

“…Normal mitochondria produce ATP to fuel cellular metabolism through oxidative phosphorylation [9]. However, damaged mitochondria liberate the proapoptotic factors, such as cyt-c, into the cytoplasm, thereby initiating caspase-9-related programmed cell death [10]. Numerous studies have identified mitochondria as potential targets to regulate the progression of renal IR injury [11-16].…”