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Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2?-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 2? (CK2?) was upregulated following acute cardiac IR injury. Increased CK2? was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2? knockout (CK2? CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2? 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 CK2? reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2? 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 CK2? serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.

SUBMITTER: Zhou H 

PROVIDER: S-EPMC5988750 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Zhou Hao H   Zhou Hao H   Zhu Pingjun P   Wang Jin J   Zhu Hong H   Ren Jun J   Chen Yundai Y  

Cell death and differentiation 20180314 6


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 (CK2α <sup>CKO</sup> ) mice were protected against IR  ...[more]

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