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Mitochondria are cytoplasmic organelles whose major function is to generate ATP by the process of oxidative phosphorylation in aerobic conditions. This process is mediated by the respiratory electron transport chain (ETC) multiprotein enzyme complexes I–V and the two electron carriers, coenzyme Q (CoQ) and cytochrome c. Other cellular processes to which mitochondria make a major contribution include apoptosis (programmed cell death), along with additional cell-type specific functions (Table e18-1). 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 for generating reactive oxygen species (ROS), whose rate of production also relates to the coupling of ATP production to oxygen consumption. In light of 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. e18-1). Thus, physicians in many specialties may encounter patients with mitochondrial diseases and should be aware of the existence and characteristics of those diseases.

Table e18-1 Functions of Mitochondria
Figure e18-1

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

The integrated activity of an estimated 1500 gene products is required for normal mitochondrial biogenesis, function, and integrity. Most of these products are encoded by nuclear genes and thus follow the rules and patterns of nuclear genomic inheritance (Chap. 63). These nuclear-encoded proteins are synthesized in the cell cytoplasm and imported to their location of activity in mitochondria through a complex biochemical process. In addition, the mitochondria have their own genome, which consists of numerous copies (polyploidy) per mitochondrion of a circular, double-strand mitochondrial DNA (mtDNA) molecule consisting of a 16,569-nucleotide sequence. This mtDNA sequence contains a total of 37 genes, of which 13 encode mitochondrial protein components of the ETC. The remaining 22 tRNA- and 2 rRNA-encoding genes are dedicated to the process of translating the 13 mtDNA-encoded proteins. This dual genetic control of mitochondrial function results in unique and diagnostically challenging patterns of inheritance. This chapter focuses on heritable traits and diseases related to the mtDNA component of the dual genetic control of mitochondrial function. The reader is referred to Chaps. 63 and 387 for consideration of mitochondrial disease originating from mutations in the nuclear genome. These mutations include (1) nuclear genomic mutations that disrupt the integrity of the mitochondrial genome itself (mtDNA deletion and depletion states), (2) disorders due to mutations in nuclear genes ...

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