27 Mitochondrial Translation and Human Disease

Most eukaryotic cells rely on oxidative phosphorylation for cellular ATP production. The machinery for oxidative phosphorylation consists of five large hetero-oligomeric enzyme complexes, located in the inner mitochondrial membrane. The majority of the approximately 85 structural components of this system are encoded in the nuclear genome, but a small number of essential protein subunits—13 in mammals—have been retained on the mitochondrial genome (mtDNA), and these are synthesized on a dedicated protein translation apparatus in the mitochondrial matrix. All of the proteins necessary for the replication, transcription, and translation of the genes encoded in mtDNA are encoded in the nuclear genome. This genetic investment is far out of proportion to the number of proteins involved, and it is likely that a small, semiautonomous mitochondrial genome has persisted because the proteins it encodes are hydrophobic proteins that need to be cotranslationally inserted into the inner mitochondrial membrane during assembly of the oxidative phosphorylation complexes. As might be expected from the α- proteobacterial origins of mitochondria, many of the features of mitochondrial translation are similar to those found in prokaryotes. In this chapter, we review the organization and control of mitochondrial translation, with a particular emphasis on the system in mammals and on mechanisms of disease. ORGANIZATION OF THE MAMMALIAN MITOCHONDRIAL TRANSLATION SYSTEM Mammalian mtDNA is a small (~16.5 kb) double-stranded circular genome that codes for 13 proteins, 22 tRNAs, and 2 rRNAs. It contains no introns, and the genetic code is different from the universal code: Nuclear arginine (AGA, AGG)...