This chapter discusses the genetic aspects of mitochondrial myopathies. Mitochondria are the major producers of cellular adenosine triphosphate (ATP) by the process of oxidative phosphorylation (OXPHOS). The mitochondrial OXPHOS system encompasses five multiple subunit enzyme complexes plus the adenine nucleotide translocator (ANT), all of which are embedded in the mitochondrial inner membrane. Four of these five OXPHOS enzyme complexes contain polypeptide subunits encoded by both the nucleus and the mitochondria. The two promoters, light strand promoter (LSP) and heavy-strand promoter (HSP), of mtDNA transcription are adjacent to each other within the displacement loop (D-loop). Inverted sequences located upstream from both promoters bind mitochondrial transcription factor (mtTFl). MtTFl is required in addition to the mitochondrial RNA (mtRNA) polymerase for efficient transcription. The genetic code of the mtDNA differs from nucleus and virtually all other organisms. The mtDNA genetic code is highly degenerate, so that only 22 tRNAs are required for translation. When uridine is in the wobble position, all 4 members of a codon family can be read by 1 mitochondrial tRNA. © 1994, ACADEMIC PRESS, INC.