**1. Introduction**

The oldest reports of intracellular structures that most likely represented mitochondria date back to 1840s [1], whereas the association of these organelles with specific biological functions essential for the hosting cells can be attributed to Altman [2]. The first utilization of the term 'mitochondrion' is attributed to Benda, in 1895 [3]. Regaud, in the early twentieth century, suggested that the organelle was constituted of protein and lipids [4], but it is not until the 1960s through the seminal work by Palade [5] and the use of electron microscopy that the structure and morphology of the organelle as it is currently known was defined. Alongside

© 2016 The Author(s). Licensee InTech. 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. © 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.

these studies, the utilization of various experimental approaches resulted in the identification of a variety of enzymes and proteins localized either within the mitochondrial matrix or associated with the inner mitochondrial membrane or the inter-membraneous space, as well as the presence of mitochondrial DNA [for an historical overview see [6] and the refs. therein]. Because the reduplication of mitochondrial DNA occurs following the reduplication of cellular DNA, and mDNA only accounts for less than half of all the mitochondrial enzymes and proteins, sophisticated biological mechanisms are in place to coordinate the import and proper allocation of mitochondrial enzymatic components within the organelle following their cellular synthesis. Furthermore, mitochondria are not static organelles but undergo constant fusion and division (fission) to form ever changing tubular networks in most eukaryotic cells. These changes are important for the normal physiology of the cell, and may dramatically affect cell behavior under pathological conditions.

vice versa. However, in addition to having a very low Km for ammonia (~1 mM), at equilibrium the reaction catalyzed by this enzyme favors ammonia and α-ketoglutarate production. Conversion of α-ketoglutarate to glutamate does occur in brain mitochondria as a

through ADP-ribosylation, but also by caloric restriction or hypoglycemia, as either of the latter two conditions increase glutamate dehydrogenase activity to increase the amount of α-ketoglutarate produced. In turn, α-ketoglutarate is used to provide energy thought the citric acid cycle, ultimately generating ATP. The activity of the enzyme does not appear to be regulated by an increase in the levels of Ca2+ and Mg2+, which can accumulate to a significant extent within mitochondria under physiological conditions. On the other hand, Zn2+ has been reported to act as an allosteric regulator of the enzyme, together with ATP and possibly GTP. *α-ketoglutarate dehydrogenase* (1.2.4.2): Also known as oxoglutarate dehydrogenase complex (OGDC), this enzymatic complex is known for its role in the citric acid cycle. Three different forms of this complex can be identified based on the specific substrate of interaction. One form is specific for pyruvate, a second one is specific for 2-oxoglutarate, and a third one is specific for branched-chain α-keto-acids. Because the same dehydrogenase subunit is utilized, the three forms of the complex utilized the same coenzymes: i.e. TTP, CoA, lipoate, FAD and NAD. Functionally, this dehydrogenase is involved in lysine degradation and tryptophan metabolism in addition to playing a key control point in the TCA cycle. In this contest, the dehydrogenase controls the level of reducing equivalents, such as NADH, generated in the cycle which, in turn increase the electrons flux through the mitochondrial electron transport chain, enhancing oxidative phosphorylation and ultimately ATP synthesis [10]. In a classic enzymatic inhibitory feedback, the activity of α-ketoglutarate dehydrogenase is inhibited by the reaction by-products succinyl-CoA and NADH, as well as by a high energy status (elevated ATP and NADH levels) within the cell, and by CoA-SH. Conversely, an increase in ADP level acts as an allosteric activator of the dehydrogenase. Calcium [10] and magnesium [11] ions also act as allosteric activators of the enzyme. The effects of Ca2+ and Mg2+ on the enzyme activity appear to be additive when the concentrations of free Mg2+ in the matrix is <1 mM. The presence of the divalent cations markedly decrease the Km for α-ketoglutarate from ~4–5 mM in the absence of Ca2+ and Mg2+, to 2.2 mM in the presence of Ca2+ alone, to 0.3 mM in the presence of both cations [11]. The effect of Mg2+ is only observed in the presence of thiamine pyrophosphate (TPP), suggesting that the enzyme requires both TPP and Mg2+ for maximal activity. The presence of both cations also decreases the affinity of the dehydro-

[11]. The modulatory effect of both Ca2+ and Mg2+ are observed at concentra-

tions that are well within the range reported to occur in mitochondria for these cations under stimulatory conditions, e.g. by catecholamine or other hormones, thus supporting the likeli-

A side product of a-ketoglutarate activity is the generation of free radicals, which can lead to oxidative stress if accumulating in high levels due to increased production and/or reduced detoxification. Due to its ability to generate free radicals, this dehydrogenase is considered de facto a mitochondrial redox sensor [12] in that it can modulate the rate of mitochondrial functioning and consequently the level of oxidative stress, thereby limiting the associated damage [12]. Under conditions in which the level of free radicals becomes extremely elevated, the enzyme can undergo a fully reversible oxidative inhibition [13]. This temporary inhibition

hood that these regulatory effects can occur under in vivo conditions.

ratio [9]. In humans, the activity of the enzyme is regulated

Physiology and Pathology of Mitochondrial Dehydrogenases

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result of local NAD<sup>+</sup>

genase for NAD<sup>+</sup>

:NADH/H<sup>+</sup>

From the functional stand-point, mitochondria are regarded as the source of energy for the cell, in that they produce a steady flow of ATP that is utilized in a variety of cellular functions and signaling events. In addition to producing ATP, mitochondria play a major role in signaling, cell differentiation and growth, cell cycle, cell death (apoptosis), and in the production of reactive oxygen species (ROS) [7].

While certain mitochondrial functions are present almost exclusively in specific cells (e.g. ammonia detoxification in hepatic mitochondria), ATP production represents the predominant and ubiquitous function of the organelle in all eukaryotic cells. The chemiosmotic coupling of proton movement out of specific sites of the electron transport chain to their re-entry through the F0-F1 ATPase, with associated ATP production in a 3H<sup>+</sup> : 1ATP ratio, as proposed by Mitchell [8] in 1966, is now generally accepted, although some details of the process need further refinement. The generated ATP is then extruded in a 1ADPin: 1ATPout ratio into the cytoplasm through the adenine nucleotide translocase (AdNT), one of the most abundant proteins present in the mitochondrial membrane.

Despite our current understanding of the mechanisms responsible for ATP synthesis within the mitochondria and its extrusion across the organelle membrane, the specific role of various mitochondrial dehydrogenases and their regulation in modulating ATP synthesis to maintain a stable and viable flow of energetic 'currency' for the cell based on the available substrate is still not completely elucidated.

The present review does not have the pretense of being comprehensive in addressing the role and regulation of all mitochondrial dehydrogenases. Rather, it will focus on the regulation of some of them, and the dysregulation occurring under specific pathological conditions, which ultimately impacts the proper functioning of specific organs or tissues.
