chapter  4
54 Pages

Oxidative Phosphorylation Disease: Diagnosis and Pathogenesis

Oxidative Phosphorylation Biochemistry and Genetics.... 249 Oxidative Phosphorylation Disease Genetics............ 252

Oxidative Phosphorylation Disease Diagnosis .................. 253 Phenotype Recognition................................................ 254 Metabolic Testing ........................................................ 257 Skeletal Muscle Pathology in OXPHOS Diseases .... 257 OXPHOS Biochemistry ............................................... 259 Genetic Testing for OXPHOS Diseases ..................... 261

Oxidative Phosphorylation Disease Classification ............ 262 MtDNA Mutations and OXPHOS Disease......................... 262

Defects in OXPHOS Enzyme Polypeptides Coded by mtDNA.............................................. 262

Defects in Mitochondrial Protein Synthesis ...................... 264 MtDNA Mutations Involving Polypeptide and

Protein Synthesis Genes: mtDNA Deletions and Duplications.............................. 264

Mitochondrial Protein Synthesis Defects: Transfer RNA and Ribosomal RNA Mutations................................................. 266

Nuclear DNA Mutations and OXPHOS Disease ............... 268 Nuclear DNA Mutations in OXPHOS Subunits....... 268 OXPHOS Cofactor Defects.......................................... 270

Defects in Intergenomic Communication ........................... 270 Defects in OXPHOS Enzyme Assembly and Processing... 275 Defects in Intracellular Movement of Mitochondria ......... 279

Mitochondrial Membrane Defects.............................. 280 OXPHOS Disease Management.......................................... 280 Summary .............................................................................. 282 References............................................................................. 282

Normal ATP generation by oxidative phosphorylation (OXPHOS) is a complex process requiring the coordinate expression of two genomes: the nuclear DNA (nDNA) and the mitochondrial DNA (mtDNA). Much of our knowledge as well as many recent questions concerning how the nDNA and mtDNA interact comes from the detailed clinical, biochemical, and genetic analysis of OXPHOS diseases. The first pathogenetic mutations in the mtDNA (1-3) were discovered approximately 7 years after the complete human mtDNA sequence was published (4). This relatively long lag time reflected, in part, some of the controversies involved in recognizing OXPHOS disease phenotypes and the complexities of mtDNA analysis. Since that time, the number of pathogenic mtDNA mutations and nuclear DNA mutations has increased dramatically, resulting in a deeper understanding of how OXPHOS genetics apply to human disease.