**11. Voltage-dependent anion channel (VDAC)**

VDAC, a channel protein localized to the outer mitochondrial membrane, conducts a variety of small metabolites (NAD+ /NADH, ADP, and ATP) and ions across the outer membrane and is a key regulator of energy metabolism [56]. VDAC forms a complex with ANT, which facilitates influx of ADP into mitochondria and the efflux of ATP to the cytoplasm [56–58]. VDAC1 closure leads to hyperpolarization of mitochondria, disruption of ADP/ATP exchange, decrease in ATP synthesis, and metabolic dysfunction, and rupture of mitochondria [56–58]. The four known VDAC isoforms present in the outer mitochondrial membrane are phosphorylated on multiple serines and threonines [21, 22]. A total of 19 distinct phosphorylations were identified in VDAC isoforms [21, 65]. These phosphorylations are mediated by different kinases including PKA, PKC, tyrosine kinase, hexokinase, GSK-3β, Akt, JNK3, and p38 [59]. The phosphorylation of neuronal and hepatic VDAC1 by PKA and ischemia-activated GSK-3β and JNK induces its closure, disrupts formation of the complex with ANT, and decreases ATP synthesis [59]. In contrast, phosphorylation of cardiac VDAC1 by protein kinase C-ε (PKC-ε) promotes formation of the VDAC-ANT complex, prevents the opening of MPTP, and protects mitochondrial integrity after I/R injury [60]. Phosphorylation of VDAC1 by never-in-mitosis A related kinase 1 (Nek1) on S193 closes the channel in RPTC, blocks release of cytochrome c, and prevents cell death by apoptosis [61]
