The Function of TIM22 in the Insertion of Inner Membrane Proteins in Mitochondria

Diverse pathways accommodate the import of proteins into the mitochondrion. In contrast to the translocase of the inner membrane 23 (TIM23) import pathway utilized by matrix-targeted proteins, the TIM22 pathway mediates the import of polytopic inner membrane proteins such as the mitochondrial carrier family and import components Tim17p, Tim22p, and Tim23p. Substrates of the TIM22 pathway lack the typical N-terminal targeting sequence and instead contain targeting information within the mature part of the protein. Components of the TIM22 pathway include the small Tim proteins, Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p, which are soluble components in the intermembrane space. Tim9p partners with Tim10p and Tim8p with Tim13p to form chaperone-like complexes and escort the precursor across the aqueous intermembrane space. At the inner membrane, the 300-kDa insertion complex consisting of Tim12p, Tim18p, Tim22p, and Tim54p and a fraction of the Tim9p and Tim10p mediates insertion into the inner membrane. The TIM22 pathway is evolutionarily conserved from yeast to plants and animals. However, homologues have not been identified in prokaryotes, suggesting that the TIM22 pathway developed after endosymbiosis. Interestingly, the first mitochondrial disease (Mohr-Traneb-jaerg or deafness-dystonia syndrome) associated with a defect in protein import is caused by loss-of-function mutations in one of the small Tim proteins, TIMM8A/DDP1. Identification of the TIM22 pathway confirms that mitochondrial protein import and assembly pathways are indeed complex