**8. Cytochrome c**

super-complexes, which reduces activity of the electron transport chain [34]. Thus, phosphorylation controls the formation, stability, and function of complex I and its assembly

Complex II is an essential regulator of metabolic reprogramming and respiratory adaptation. Mitochondrial Src-type tyrosine kinase Fgr phosphorylates complex II on Y535, Y596, and Y604 when activated by ROS generated by I/R [32]. Phosphorylation of Y604 on the flavoprotein subunit of succinate dehydrogenase (FpSDH) increases activity of complex II and serves as a metabolic adaptation to increased ROS production [32, 34]. Fgr-mediated phosphorylation also reduces the protein levels of complex I, which alters the mitochondrial preference

chondria to utilize alternative fuels when complex I is impaired [32]. Blocking phosphorylation of FpSDH on Y604 abolishes the capacity of mitochondria to adapt their metabolism after hypoxia/reoxygenation [32]. Mitochondrial phosphatases dephosphorylate Y604 and reverse this metabolic adaptation [32, 34]. In contrast, phosphorylation of FpSDH in cancer cells undergoing hypoxia decreases and dephosphorylation of FpSDH increases SDH activity [35]. Our data show that the activity of complex II in injured renal proximal tubular cells (RPTC) and in the ischemic kidney cortex is unchanged, whereas the activity of complex I is decreased [25, 36]. Supplementing the RPTC with succinate (complex II substrate) ameliorates mitochondrial dysfunction, ATP deficits, oxidative stress, and cell death after injury associ-

Phosphorylation has been implicated in the regulation of the Rieske iron-sulfur protein of complex III, which is a major target of ischemia and the decreases in its activity lead to increased superoxide production [37]. Several phosphorylation sites have been identified on the subunits of complex III. The tyrosines on the core subunit 1 of complex III are phosphorylated by the Src kinase family, but the functional consequence of this phosphorylation is not yet known [38]. The role of phosphorylation of Rieske iron-sulfur protein is not clear and it

To date, 14 phosphorylation sites have been mapped on complex IV [39]. Tyrosine phosphorylation of the specific subunits of complex IV can lead to both inhibition and activation of complex IV activity [39, 40]. Bender and Kadenbach have shown phosphorylation of complex IV subunits I, II/III, and Vb *in vitro* [41]. cAMP-dependent phosphorylation of Y304 on the catalytic subunit I inhibits, whereas tyrosine phosphorylation of subunit II by

, which increases the metabolic capacity of mito-

**5. Succinate-ubiquinone oxidoreductase (complex II)**

into super-complexes.

186 Mitochondrial Diseases

for fuel oxidation from NADH to FADH2

ated with the generation of ROS and oxidative stress [36].

was suggested that it regulates the MPTP opening [37].

**7. Cytochrome oxidase (complex IV)**

**6. Ubiquinol-cytochrome c oxidoreductase (complex III)**

Phosphorylations of serine, threonine, and 2 tyrosine residues have been mapped on cytochrome c [39, 47]. Phosphorylation of T28 results in a partial inhibition of the electron transport chain and respiration [48]. It was suggested that the other phosphorylations regulate the mobility of cytochrome c between complexes, its binding to cardiolipin, and the interaction with Apaf-1 during apoptosis [47].

#### **9. ATP synthase (Fo F1 -ATPase)**

Multiple and differential phosphorylations of ATP synthase have been reported in different organisms and tissues. Tyrosine phosphorylations of the ε-subunit (in the F<sup>o</sup> domain) and the α- and δ-subunits of the F<sup>1</sup> domain are mediated by Src kinase [49, 50]. The α and e subunits of Fo F1 -ATPase in mammalian brain are phosphorylated on S76 and Y32 [51]. The catalytic β-subunit is extensively phosphorylated on S106, T107, T262/S263, T312, and T368 in mammalian cardiomyocytes, whereas in yeast, the β-subunit is phosphorylated on T58, S213, T262, and T318 [51]. These phosphorylations affect assembly of the F<sup>1</sup> domain and reduce ATP synthase activity [51]. They occur in cardiac preconditioning, which offers protection against ischemia [51]. Phosphorylation of T213 on the β-subunit of skeletal muscle F<sup>o</sup> F1 -ATPase downregulates its levels *in vivo* [6, 51]. We have shown serine phosphorylations on the α and/or β- and γ-subunits of ATP synthase in RPTC [52]. These phosphorylations are PKC-αdependent and preserve the levels of the γ-subunit and F<sup>o</sup> F1 -ATPase activity in injured renal cells [52]. Phosphoproteomics demonstrated phosphorylation of S146 on the γ-subunit [52]. Phosphorylation of the γ-subunit is associated with the formation of ATP synthase dimers [52].
