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
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Table e18-1 Functions of Mitochondria
|All Cells and Tissues|
Apoptosis (programmed cell death)
|Tissue- or Cell-Specific|
Amino and organic acid metabolism
Fatty acid beta oxidation
Sex steroid synthesis
Hepatic ammonia detoxification
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 that encode structural components or assembly factors of the oxidative phosphorylation complexes, and (3) mitochondrial disorders due to mutations in nuclear genes that encode proteins indirectly related to oxidative phosphorylation.
As a result of its circular structure and extranuclear location, the replication and transcription mechanisms of mtDNA differ from the corresponding mechanisms in the nuclear genome, whose nucleosomal packaging and structure are more complex. Since each mitochondrion contains many copies of mtDNA and because the number of mitochondria can vary during the lifetime of each cell through the processes of fission, fusion, and mitochondrial biogenesis, mtDNA copy number is not directly coordinated with the cell cycle. Thus, vast differences in mtDNA copy number are observed between different cell types and tissues and during the lifetime of a cell. Another important feature of the mtDNA replication process is a greatly reduced stringency of proofreading and replication error correction, leading to a greater degree of sequence variation compared with the nuclear genome. This fidelity limitation is due to the presence of one replicase, polymerase γ, which is solely responsible for both DNA replication and repair in mitochondria. Some of these sequence variants are silent polymorphisms that do not have the potential for a phenotypic or pathogenic effect, whereas others may be considered pathogenic mutations.
With respect to transcription, initiation can occur on both strands and proceeds through the production of an intronless polycistronic precursor RNA that then is processed to produce the 13 individual mRNA and 24 individual tRNA and rRNA products. The 37 mtDNA genes account for fully 93% of the 16,569 nucleotides of the mtDNA in what is known as the coding region. The control region consists of ~1.1 kilobases (kb) of noncoding DNA that is thought to play a major role in replication and transcription initiation. The mutation rate is considerably higher in the control region, which contains a displacement, or D loop, which in turn contains two adjacent hypervariable regions (HVR-I and HVR-II) that give rise to large interindividual variability within the human population. Indeed, mtDNA sequence variants at both the coding and control regions are more highly partitioned across geographically defined populations than are sequence variants in other parts of the genome, and combinations of these sequence variants define phylogeographic mtDNA haplogroups and haplotypes. Accumulating evidence supports the notion that differences in these haplotypes are of medical significance in regard to predisposition to common diseases. The foregoing structural and functional features of mtDNA lead to the expectation that phenotypic inheritance and disease patterns for disorders related to mtDNA sequence variations and mutations should be quite different from the more familiar inheritance and disease patterns attributed to variation and mutation in nuclear DNA. Intensive research during the last two decades has confirmed that this is the case.
Maternal Inheritance and Lack of Recombination
In contrast to the homologous pair recombination that takes place in the nucleus, mtDNA molecules do not undergo recombination, and so mutational events ...