Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy

Abstract

Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2αCKO) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivation) of FUN14 domain containing 1 (FUNDC1) via post-transcriptional modification at Ser13, thus effectively inhibiting mitophagy. Defective mitophagy failed to remove damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inhibition, mitochondrial biogenesis arrest, cardiolipin oxidation, oxidative stress, mPTP opening, mitochondrial debris accumulation and eventually mitochondrial apoptosis. In contrast, loss of CK2α reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2α and FUNDC1 failed to show protection against IR injury and mitochondrial damage through a mechanism possible attributed to lack of mitophagy. Taken together, our results confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.

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

“…Excessive mitochondrial fission and mitophagy arrest produce numerous mitochondrial fragments, stimulating ROS overproduction, mPTP opening, cyt-c leakage, and caspase-9 activation [17,18,31,65]. We also identified NR4A1 as the regulator of hyperglycemiamediated fission augmentation and mitophagy delay because deletion of NR4A1 repressed the formation of mitochondrial fragmentation and promoted mitochondria fusion with lysosomes.…”

“…However, the upstream regulatory molecule for Mff-required mitochondrial fission in the setting of DN remains unknown. In response to mitochondrial fission, mitochondria could employ lysosomes via Parkin to degrade damaged mitochondria and maintain a healthy mitochondrial population, which is essential for cell survival [18][19][20]. Notably, the impairment of Parkin-mediated mitophagy is a feature of DN, and various pharmacological activators of mitophagy have been shown to protect against glomerulosclerosis and proteinuria, renal hypertrophy, and mesangial expansion in rodent DN models [21][22][23].…”

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

“…After being washed with binding buffer, the cells were analyzed by fluorescence microscopy. Results are presented as relative aggregate‐to‐monomer (red/green) fluorescence intensity ratio …”

“…In contrast to mitochondrial fission, mitochondrial fusion promotes communication between mitochondria, repressing the formation of mitochondrial fragmentation and sustaining mitochondrial genomic homeostasis . Moreover, mitochondrial fusion enhances the activity of mitophagy, and the latter is an evolutionally conserved catabolic pathway that clears damaged mitochondrial fragmentation . Thus, cells with well‐orchestrated mitochondrial fusion and mitophagy are able to sequester dysfunctional mitochondria .…”

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

“…Mitochondria are the center of cell energy production and the triggers of programmed cell death [7, 8]. Normal mitochondria produce ATP to fuel cellular metabolism through oxidative phosphorylation [9].…”