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.
Highlights
We uncover that (1) casein kinase 2α (CK2α) is progressively increased in the reperfused heart, which is instrumental for scar expansion and cardiac dysfunction in response to ischemia reperfusion (IR) injury; (2) functional assays illustrate that higher CK2α expression renders cardiomyocytes to mitochondrial apoptosis via post-transcriptional inactivation of FUN14 domain containing 1 (FUNDC1), leading to the inhibition of protective mitophagy; (3) defective mitophagy fails to remove the damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inactivity, cardiolipin oxidation and mitochondrial apoptosis; (4) loss of cardiac CK2α sustains heart function and structure under IR injury, (5) genetic ablation of FUNDC1 abolishes the protection observed in CK2α deletion in vivo and in vivo
FUNDC1-required mitophagy was suppressed via reperfusion by way of CK2α, leading to the progression of IR injury
Previous studies have confirmed the harmful effects of CK2α on chronic cardiac injury including diabetic cardiomyopathy [23] and heart failure [24], its detailed molecular machinery related to mitochondrial etiology in cardiac IR injury remains largely unexplored
Summary
One of the hallmarks of cardiac ischemia reperfusion (IR) injury is the altered architecture and function of mitochondria [1]. Accumulating evidence has depicted an indispensable role of mitophagy in mitochondrial protection [4]. The mitochondrialspecific analog to autophagy, is considered a beneficial metabolic event and is pivotal to the preservation of mitochondrial quality [5]. Evidence from our group has shown that enhanced mitophagy alleviates mitochondrial oxidative stress, preserves mitochondrial respiratory function, limits mitochondrial debris formation, and blocks caspase 9related apoptosis [3,6,7,8,9]. Mitophagy is proposed to be a mechanistic requirement of cellular survival in cardiac IR injury and could be a promising target to relieve the IR attack [10]
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