**1. Introduction**

Ischemia (insufficient oxygen and nutrient supply to an organ) can affect all major organs and is often encountered in many clinical and nonclinical settings including myocardial infarction, stroke, pulmonary embolism, major surgery, tissue trauma and hemorrhage, transplantation

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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and organ storage, or hypotension in septic shock. Functional deficits caused by ischemia in major organs result in significant morbidity, disability, and mortality. Mitochondria are double-membrane-bound, dynamic organelles present in most eukaryotic cell types. They require large amounts of oxygen to generate ~90–95% of the total energy in oxidative phosphorylation occurring in a majority of cells [1]. Therefore, mitochondria are the key subcellular targets of ischemia, which undergo pathological changes that trigger cellular and tissue damage when oxygen is unavailable. Mitochondria perform several major cellular functions including energy and intermediary metabolisms, several biosyntheses, regulation of calcium storage, and redox homeostasis [1]. They are also involved in signaling, cell cycle, growth, differentiation, and cell death by apoptosis [2].

**3. Phosphorylation of mitochondrial proteins as a regulatory mechanism** 

Protein Kinases and Regulation of Mitochondrial Function in Ischemia/Reperfusion Injury

http://dx.doi.org/10.5772/intechopen.71094

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Numerous mitochondrial proteins (354 reported to date) are phosphoproteins that collectively contain 899 identified and 479 potential novel phosphorylation sites [18, 19]. Consequently, phosphorylation of mitochondrial proteins has emerged as an important mechanism involved in progressive damage of mitochondria in response to metabolic stresses including I/R and the status of these phosphorylations is key to understanding the regulation of mitochondrial functions in disease states [18, 19]. A number of protein kinases localize to mitochondria in response to I/R [19, 20]. Protein phosphorylations by these kinases produce differential outcomes in different tissues depending on the phosphorylation site and the kinase involved. The key proteins of oxidative phosphorylation, TCA cycle, transport, and the cascade of intrinsic

The largest group of phosphorylation sites was found among proteins involved in oxidative

Dysfunction of complex I is the most common disorder of oxidative phosphorylation in humans. It is often due to defects of the subunit assembly to form the mature complex I. Complex I is a major mitochondrial target of I/R. Its activity decreases as early as 10 minutes into cardiac ischemia [24]. Our studies demonstrated that the activity of complex I in renal cortical mitochondria is decreased after renal ischemia [25]. Changes in the activity of complex I during I/R are also regulated by phosphorylation [4, 26]. Phosphorylations occur on several subunits of complex I. The NDUFA10 subunit is phosphorylated on S59 and S95 [27]. The NDUFS4 and NDUFA10 subunits are phosphorylated by mitochondrial protein kinase A (PKA), which stimulates the activity of complex I [27–29]. Phosphorylations of subunit ESSS on S20 and subunit MWFE (NDUFA1) on S55 regulate complex I assembly. Blocking these phosphorylations inhibits assembly of subunits to form a mature complex I and reduces its activity [26, 30]. Tyrosine phosphorylation of the NDUFB10 subunit by Src kinases also increases the activity of complex I, possibly by increasing its affinity toward NADH or increasing assembly of subunits into the fully active complex I [31, 32]. The reduced assembly of subunits leads to decreased levels of complex I [32]. This adaptation shifts fuel utilization from fuels that generate primarily NADH (carbohydrates) to

during nutritional restriction or after ischemic injury [32]. Further, complex I is primar-

and reduces ROS production [33]. Cardiac I/R induces disintegration of mitochondrial

ily assembled into mitochondrial super-complexes, which increases O2

(fatty acids) oxidized by complex II. This shift may occur

consumption

**of energy metabolism during ischemia/reperfusion**

apoptosis are regulated by phosphorylation [19–23].

fuels generating more FADH2

**3.1. Phosphorylation of proteins involved in oxidative phosphorylation**

**4. NADH-ubiquinone oxidoreductase (complex I)**

phosphorylation: respiratory complexes, ATP synthase, ANT, and VDAC [18, 19].
