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INTRODUCTION

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Mitochondria are cytoplasmic organelles whose major function is to generate ATP by the process of oxidative phosphorylation under aerobic conditions. This process is mediated by the respiratory electron transport chain (ETC) multiprotein enzyme complexes I–V and the two electron carriers, coenzyme Q10 (CoQ10) and cytochrome c. Other cellular processes to which mitochondria make a major contribution include apoptosis (programmed cell death) and additional cell type-specific functions (Table 472-1). The efficiency of the mitochondrial ETC in ATP production is a major determinant of overall body energy balance and thermogenesis. In addition, mitochondria are the predominant source of reactive oxygen species (ROS), whose rate of production also relates to the coupling of ATP production to oxygen consumption. Given the centrality of oxidative phosphorylation to the normal activities of almost all cells, it is not surprising that mitochondrial dysfunction can affect almost any organ system (Fig. 472-1). Until recently, it was thought that disruption of energy production was the source of the pathophysiology in those with mitochondrial dysfunction, but recent evidence suggests that free-radical production and the redox state of the mitochondria may play a role as well. Thus, physicians in many disciplines might encounter patients with mitochondrial diseases and should be aware of their existence and characteristics.

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TABLE 472-1Functions of Mitochondria
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FIGURE 472-1

Dual genetic control and multiple organ system manifestations of mitochondrial disease. (Reproduced with permission from DR Johns: Mitochondrial DNA and disease. N Engl J Med 333:638, 1995.)

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The integrated activity of estimated 1500 gene products is required for normal mitochondrial biogenesis, function, and integrity. Aside from the 37 genes that comprise the mitochondrial DNA (mtDNA) molecule, the remaining 1400+ gene products are encoded by nuclear genes (referred to as nDNA) and thus follow the rules and patterns of nuclear genomic inheritance (Chap. 456). These nuclear-encoded proteins are synthesized in the cell cytoplasm and imported to their location of activity within the mitochondria through a complex biochemical process. This process includes unfolding of the nuclear-encoded protein, attachment to a chaperone protein that shuttles it through a specific channel to a specific mitochondrial location, and detachment from the chaperone followed by assembly with other mtDNA- and nDNA-encoded proteins. In addition, the mitochondria contain their own small genome consisting of numerous copies (polyploidy) per mitochondrion of a circular, double-strand mitochondrial DNA (mtDNA) molecule comprising 16,569 nucleotides. This mtDNA sequence (also known as the “mitogenome”) might represent the remnants of endosymbiotic prokaryotes from which mitochondria are thought to have originated. The mtDNA ...

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