**12.1. Protein kinases regulating large dehydrogenase complexes**

A specific family of protein kinases is exclusively present in the mitochondrial matrix of eukaryotic cells. These kinases have different sequences from the cytosolic protein kinases and they phosphorylate and inactivate large enzymatic complexes in the mitochondrial matrix, the branched-chain α-ketoacid dehydrogenase complex and pyruvate dehydrogenase complex, PDC. Perturbations in PDC activity result in energy deficits, neuronal dysfunction, and brain injury, such as those observed in stroke. Phosphorylation of the E1 α-subunit of PDC by PDK isozymes inhibits, whereas dephosphorylation increases PDC activity [82]. Cardiac and cerebral ischemia has no effect on the activity of PDC; however, reperfusion results in a fast decline in PDC activity in the brain [83]. Increased expression of PDK2 following traumatic brain injury may maintain E1 in the hyperphosphorylated (inactive) state, which impairs glucose oxidation after stroke and traumatic brain injuries [83]. Further, reperfusion-induced oxidative stress activates PKC-δ, which translocates to mitochondria and activates PDK2 leading to inhibition of E1 activity [84]. The inhibition of PDK during reperfusion restores PDC activity and decreases brain injury, demonstrating that phosphorylation by PDK2 mediates inhibition of PDC activity [85]. Infusion of the specific peptide inhibitor of PKC-δ, Tat-δV1-1, prevents the translocation of PKC-δ to mitochondria and maintains PDC activity [84]. Isozymes of PDK are considered attractive targets for therapies to improve PDC activity to diminish the detrimental effects of I/R in tissues that depend on metabolism of glucose, such as neuronal and cardiac tissues.
