Mitochondrial Disease

Background

Mitochondria produce adenosine triphosphate (ATP) by oxidative phosphorylation through the electron transport chain, which is composed of five enzyme complexes located on the inner mitochondrial membrane ( Fig. 14-1 ). Reduction of molecular oxygen is coupled to phosphorylation of adenosine diphosphate (ADP), resulting in ATP synthesis. The reduced cofactors NADH and FADH ₂ , generated by the Krebs cycle and by fatty acid oxidation, donate electrons to complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase). Electrons are then transferred to coenzyme Q and subsequently to complex III. From complex III, reduced cytochrome c donates its electrons to complex IV (cytochrome- c oxidase), resulting in the reduction of molecular oxygen to water. Complexes I, III, and IV actively pump hydrogen ions (H ⁺ ) across the inner membrane of the mitochondrion into the intermembrane space, creating an electrochemical gradient. Influx of protons back into the mitochondrial matrix through complex V results in ATP synthesis. This process of oxidative phosphorylation is the major intracellular source of the free radicals (O ₂ ⁻ , H ₂ O ₂ , and OH ⁻ ) that are generated as byproducts of the interaction between excess electrons and oxygen.

The enzymes, membranes, and other molecular components of these five major enzyme/protein complexes needed for mitochondrial oxidative phosphorylation are encoded in a complementary manner by the circular genome found within the mitochondrion itself, as well as by the much larger nuclear genome of the host cell. The mitochondrial genome encodes for 13 essential subunits of the electron transport chain, two types of ribosomal ribonucleic acid (rRNA), and 22 forms of transfer RNA (tRNA). Each mitochondrion contains multiple copies of mitochondrial deoxyribonucleic acid (mtDNA). Nuclear DNA (nDNA) encodes an additional 900 proteins that are needed for normal mitochondrial function.

The complementary relationship between two genomes within each cell and the putative evolution of the mitochondrion from a free-living organism into an organelle within the cell have been known and discussed by cell biologists only within the past three or four decades. The implications of this biologic curiosity with regard to our understanding of embryology, evolution, aging, and even the mechanism of death itself may be profound. The mitochondrion, through a central role in the modulation of bioenergetics and cellular apoptosis, may also serve as both a “biosensor” for oxidative stress and as the final determinant of cellular viability.

The most severe inherited mitochondrial disease syndromes become clinically apparent during infancy, but a few were eventually described in which symptoms did not appear until early adulthood. The original descriptions of the mitochondrial diseases of childhood assumed that there was maternal transmission of mitochondria and of both normal (“wild type”) and mutant mtDNA. Because mutant mtDNA coexists with wild-type mtDNA, variability in the severity of all these inherited conditions is thought to reflect heteroplasmy, the random differences in the proportion of mutant mtDNA distributed throughout the target tissues during embryogenesis. For the mitochondrial disorders of adult onset, variability in disease severity and an exceptionally wide range of phenotypic symptom patterns are thought to reflect both heteroplasmy and the much different, progressively changing metabolic demands of target tissues during adulthood. Hundreds of mtDNA mutations have already been identified in detail and classified as mitochondrial myopathies, encephalomyopathies, or cytopathies.

A report of a patient with mutated mtDNA of paternal origin, however, suggests that some paternal mtDNA also survives in the zygote and therefore may also contribute to the mtDNA pool. Recently, the important role of defects in nDNA in disorders characterized by declining mitochondrial bioenergetics has also been clarified, reflecting a better understanding of the interaction between nuclear and mitochondrial genomes. It is now clear that there are subunits of the electron transport chain not encoded by mtDNA that arise from nDNA. Diseases caused by nuclear genes that do not encode subunits but affect mtDNA stability are an especially interesting group of mitochondrial disorders. In these syndromes, a primary nuclear gene defect causes secondary mtDNA information loss or deletion, which leads to subsequent tissue dysfunction in the form of disrupted oxidative phosphorylation. Therefore, some genetically determined defects in oxidative phosphorylation follow classic mendelian patterns of dominant recessive genetic transmission rather than the maternal patterns usually associated with mtDNA defects.

Effect of anesthetics on mitochondrial function

The effects of anesthetics on mitochondrial function were first investigated in the 1930s. Although all the mechanisms of action are still not established, virtually all volatile, local, and intravenous (IV) anesthetics clearly have significant depressant effects on mitochondrial energy production. These effects are believed to occur primarily at the level of the electron transport chain on the inner membrane of mitochondria. Early studies reported inhibition of the oxidation of glucose, lactate, and pyruvate by narcotics, and more recent work explores the mechanism of reduced oxygen consumption in the brain after treatment with barbiturates. A common final pathway of depressed bioenergetic activity, possibly through intracellular or mitochondrial mechanisms, may also help explain the primary anesthetic effects of these drugs.

However, these data must be interpreted cautiously, because much of the work examining anesthetic-induced mitochondrial dysfunction has been done in vitro, in isolated mitochondria, and not in functioning cells. Furthermore, the anesthetic concentrations used to inhibit mitochondrial function experimentally have been up to 10-fold higher than concentrations used clinically, although anesthetics seem to inhibit mitochondria in a dose-dependent manner. The reader must take these major limitations into consideration when reviewing the subject.