Mitochondria are very complex organelles located in virtually all cells of the body. They perform a variety of functions such as intracellular signaling of oxygen tension and key roles in programmed cell death. From a biochemical perspective, mitochondria are the key site of energy production in the cell. Indeed they are the site of beta oxidation (see Chapter 55), the Krebs cycle, and parts of the urea cycle (see Figure 53-4). This complexity requires more than 1000 proteins localized specifically to the mitochondrion. Only 13 of these are encoded by the mitochondrial DNA (mtDNA); the remainder are nuclear encoded (on the chromosomes) and require import into the mitochondrion. In addition, the mitochondrial DNA needs its own set of proteins to allow for its maintenance, transcription, and translation.
Mitochondrial disorders are typically defined as defects in the ability to generate energy from oxidative phosphorylation to produce ATP by transferring electrons formed by glycolysis and the Krebs cycle to a cascade that generates NADH and FADH2 (Fig. 57-1) and are also known as phosphorylation disorders or respiratory chain disorders. The more dependent on energy production an organ is, the more profound the symptoms of deficiency of mitochondrial function in that organ. Certain proteins are only expressed in specific tissues, and defects in these will lead to differing patterns of disease. Taken together, mitochondrial disorders may affect as many as 1 in 2500 people.
Figure 57-1 The mammalian mitochondrial genome and its protein-coding gene repertoire involved in the oxidative phosphorylation pathway.
(A) Schematic representation of genes within mammalian mitochondrial genome (∼7000 bp). Genes on the outer circle are transcribed from the light strand. Location of the tRNAs (red boxes) conforms to the canonical placental mammalian arrangement. (B) Simplified view of the mitochondrial oxidative phosphorylation machinery. Complexes I (NADH dehydrogenase) and II (succinate dehydrogenase) receive electrons from either NADH or FADH2. Electrons are then carried between complexes by the carrier molecules coenzyme Q/ubiquinone (UQ) and cytochrome c (CYC). The potential energy of these electron transfer events is used to pump protons against the gradient, from the mitochondrial matrix into the intermembrane space [complexes I and III (cytochrome bc1) and IV (cytochrome c oxidase)]. ATP synthesis by complex V (ATP synthase) is driven by the proton gradient and occurs in the mitochondrial matrix. HSP, Putative heavy-strand promoter; IM, intermembrane space; MM, mitochondrial matrix; OHR, origin of heavy-strand replication; OLR, origin of light-strand replication. (From da Fonseca RR, Johnson WE, O’Brien SJ, et al: The adaptive evolution of the mammalian mitochondrial genome, BMC Genomics 9:119, 2008.)