Mitochondrial protein import and human health and disease

Abstract

The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans is dependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targeting signals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in the chaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown to lead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be a dynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This review focuses on how mitochondrial protein import affects human health and disease.

Figure 1. Mitochondrial Protein Import Pathways

Most mitochondrial proteins are predicted to be synthesized in their entirety in the cytosol and are then imported post-translationally. Proteins are maintained in an import-competent state by cytosolic chaperones and are specifically targeted to receptors at the mitochondrial surface. Proteins are then transferred from the receptors to the general import pore of the outer membrane, the TOM complex. Once across the outer membrane, proteins are sorted to one of the four intra-mitochondrial locations. Outer membrane proteins are inserted into the membrane either by the TOM or the sorting and assembly machinery (SAM) complex. Matrix proteins are sorted via the TIM23 complex and the presequence translocase-associated motor (PAM), while some single-pass inner membrane proteins are directly inserted into the membrane. Once matrix proteins cross the inner membrane, they are processed and folded via mitochondrial processing peptidase (MPP) and matrix chaperonins, respectively. Some single-pass inner membrane proteins are re-exported via OXA after being imported into the matrix. Polytopic inner membrane proteins are guided across the intermembrane space by the small Tim proteins (Tim9/10, Tim8/13) to the TIM22 complex where they are inserted into the inner membrane. The red stars denote import factors that either cause a disease state, or represent acquired changes.