Protein kinase Cα mediates recovery of renal and mitochondrial functions following acute injury.
Protein kinase Cα mediates recovery of renal and mitochondrial functions following acute injury.
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蛋白激酶 Cα 介导急性损伤后肾脏和线粒体功能的恢复。
DOI：
10.1111/febs.15110
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Megyesi,Judit
中科院分区：
文献类型：
--
作者：
Nowak,Grazyna;Megyesi,Judit
之前，我们已经证明活性蛋白激酶Cα（PKCα）促进体外损伤后线粒体功能的恢复[Nowak G & Bakajsova D（2012）Am J Physiol Renal Physiol 303，F515-F526]。本研究检测了PKCα是否调节体内缺血诱导的急性损伤（阿基）后线粒体和肾脏功能的恢复。在野生型（WT）小鼠中，双侧缺血后肾损伤标志物增加并恢复至正常水平。缺血后，WT小鼠的最大线粒体呼吸和呼吸复合物及FoF 1 ‐ATPase活性降低，并恢复。缺血再灌注后，活性PKCα向线粒体转位。PKCα缺失降低了未损伤肾脏的线粒体呼吸以及呼吸复合物I和FoF 1-ATP酶的活性，表明PKCα在发育完全功能的肾脏线粒体中至关重要。PKCα缺陷小鼠的这些变化伴随着复合物I亚基（NDUFA 9和NDUFS 3）和FoF 1-ATP酶γ亚基水平的降低。此外，PKCα的缺乏加剧了缺血诱导的呼吸、复合物I和FoF 1-ATP酶活性的降低，并阻碍了它们在损伤后的恢复，表明PKCα在促进阿基后线粒体恢复中起着至关重要的作用。此外，由于肾线粒体中脱乙酰酶和脱琥珀酸酶（sirtuin 3和sirtuin 5）水平降低，PKCα缺失加剧了缺血后能量代谢关键线粒体蛋白的乙酰化和琥珀酰化。因此，我们的数据显示PKCα在调节线粒体sirtuins水平以及关键线粒体蛋白的乙酰化和琥珀酰化中具有新的作用。我们的结论是PKCα缺失：（a）通过降低线粒体最大呼吸能力影响肾脏生理;（B）阻断AKI后线粒体功能、肾形态和功能的恢复;和（c）降低阿基后的存活率2.7.11.13泛醌还原酶（H+-易位;复合物I）：EC 7.1.1.2; FoF 1-ATP酶（H+转运双扇区ATP酶）：EC 7.1.2.2;琥珀酸盐：泛醌氧化还原酶（复合物II）：EC 1.3.5.1;泛醇：细胞色素转化酶（复合物III）：EC 7.1.1.8;细胞色素氧化酶（复合物IV）：EC 1.9.3.1; NAD依赖性蛋白脱乙酰酶sirtuin-3，线粒体：EC 2.3.1.286; NAD依赖性蛋白脱乙酰酶sirtuin-5，线粒体：EC 3.5.1. -;蛋白酶K（肽酶K）：EC 3.4.21.64。
Previously, we have shown that active protein kinase Cα (PKCα) promotes recovery of mitochondrial function after injuryin vitro[Nowak G & Bakajsova D (2012) Am J Physiol Renal Physiol 303, F515‐F526]. This study examined whether PKCα regulates recovery of mitochondrial and kidney functions after ischemia‐induced acute injury (AKI)in vivo. Markers of kidney injury were increased after bilateral ischemia and returned to normal levels in wild‐type (WT) mice. Maximum mitochondrial respiration and activities of respiratory complexes and FoF1‐ATPase decreased after ischemia and recovered in WT mice. Reperfusion after ischemia was accompanied by translocation of active PKCα to mitochondria. PKCα deletion reduced mitochondrial respiration and activities of respiratory complex I and FoF1‐ATPase in noninjured kidneys, indicating that PKCα is essential in developing fully functional renal mitochondria. These changes in PKCα‐deficient mice were accompanied by lower levels of complex I subunits (NDUFA9 and NDUFS3) and the γ‐subunit of FoF1‐ATPase. Also, lack of PKCα exacerbated ischemia‐induced decreases in respiration, complex I and FoF1‐ATPase activities, and blocked their recovery after injury, indicating a crucial role of PKCα in promoting mitochondrial recovery after AKI. Further, PKCα deletion exacerbated acetylation and succinylation of key mitochondrial proteins of energy metabolism after ischemia due to decreases in deacetylase and desuccinylase (sirtuin3 and sirtuin5) levels in renal mitochondria. Thus, our data show a novel role for PKCα in regulating levels of mitochondrial sirtuins and acetylation and succinylation of key mitochondrial proteins. We conclude that PKCα deletion: (a) affects renal physiology by decreasing mitochondrial capacity for maximum respiration; (b) blocks recovery of mitochondrial functions, renal morphology, and functions after AKI; and (c) decreases survival after AKI.EnzymesProtein kinase C: EC 2.7.11.13; NADH : ubiquinone reductase (H+‐translocating; complex I): EC 7.1.1.2; FoF1‐ATPase (H+‐transporting two‐sector ATPase): EC 7.1.2.2; Succinate : ubiquinone oxidoreductase (complex II): EC 1.3.5.1; Ubiquinol : cytochrome‐creductase (complex III): EC 7.1.1.8; Cytochromecoxidase (complex IV): EC 1.9.3.1; NAD‐dependent protein deacetylase sirtuin‐3, mitochondrial: EC 2.3.1.286; NAD‐dependent protein deacetylase sirtuin‐5, mitochondrial: EC 3.5.1.‐; Proteinase K (peptidase K): EC 3.4.21.64.