Chapter 104

## Abstract

Abstract

1. Oxidative phosphorylation (OXPHOS) is composed of five intramitochondrial enzyme complexes (complexes I to V) that are responsible for producing the majority of the ATP required for normal cellular function. Assembly and maintenance of OXPHOS requires the coordinate regulation of nuclear DNA and mitochondrial DNA (mtDNA) genes. The mtDNA encodes 12 OXPHOS subunits, 22 tRNAs, and 2 rRNAs, which provide the core elements for OXPHOS function and mitochondrial protein synthesis. The nuclear DNA is responsible for synthesizing approximately 70 OXPHOS subunits, transporting them to the mitochondria via chaperone proteins, ensuring their passage across the mitochondrial inner membrane, and coordinating their proper processing and assembly. OXPHOS is regulated by a wide variety of factors and processes that include hormone levels, oxygen supply, ion gradients, membrane transporters such as the adenine nucleotide translocase that supplies ADP for conversion to ATP, transcription factors that alter the levels of nuclear gene transcription, tissue-specific isoforms, developmental-specific isoforms, mitochondrial replication, mitochondrial transcription, and mitochondrial translation. Defects in any of these processes may produce an OXPHOS disease.

2. The cytoplasmic location of the mtDNA creates a unique genetics. Mitochondrial genetics is defined by these principles: maternal inheritance, replicative segregation, threshold expression, a high mtDNA mutation rate, and a propensity to accumulate somatic mutations with age. The age-related accumulation of mtDNA mutations may contribute to the decline of cellular OXPHOS function with age and to the progression of a variety of degenerative diseases. Increases in somatic mtDNA mutations are associated with increased generation of free radicals that permanently damage the mtDNA. The paucity of mtDNA repair mechanisms means that once mtDNA damage occurs, the mutated mtDNA can persist in the cell and clonally proliferate over time. After sufficient levels of mutant mtDNA are reached, OXPHOS function begins to decline.

3. mtDNA mutations are classified as deletions, duplications, or point mutations. These mutations produce defective OXPHOS subunits or abnormalities in mitochondrial protein synthesis. Mutations in nuclear OXPHOS genes are the most important causes for OXPHOS diseases. These mutations have diverse effects that include increases in the mtDNA mutation rate, decreases in the mtDNA copy number, impaired OXPHOS enzyme assembly, and abnormal function of an OXPHOS enzyme subunit.

4. OXPHOS diseases are a complex family of disorders with a vast array of clinical manifestations that can be caused by mutations in the nuclear DNA or the mtDNA. OXPHOS mutations produce diseases that can affect a variety of developmental stages, tissues, or systems, resulting in a diversity of clinical phenotypes encountered in virtually all age groups. Hence, OXPHOS diseases should be considered in the differential diagnosis of many familial diseases. The evaluation of patients for OXPHOS diseases is complex and should be performed at centers that are experienced with the clinical, biochemical, and genetic characteristics of these disorders. The principles of mitochondrial genetics, as well as of Mendelian genetics, must be considered when interpreting the results of this analysis. This approach permits developing an appropriate management plan, addressing genetic counseling issues for the family, focusing on anxieties associated with the complexities of these diseases processes, providing patient education, and minimizing the need for further complex and expensive diagnostic evaluations.

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