Previously, we have shown that active
protein kinase Cα (PKCα) promotes recovery of mitochondrial function after injury in 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 Fo
F1 -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 Fo
F1 -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 Fo
F1 -ATPase. Also, lack of PKCα exacerbated
ischemia-induced decreases in respiration, complex I and Fo
F1 -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.
ENZYMES:
Protein 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-c
reductase (
complex III): EC 7.1.1.8;
Cytochrome c oxidase (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.