Mitochondrial Protein Import in Fungi and Animals

Abstract

Mitochondria are essential constituents of virtually all eukaryotic cells. They represent the major production site of chemical energy in the form of ATP, and house a number of essential biosynthetic pathways. In recent years, mitochondria have been identified as key components of signaling pathways. As endosymbiotic organisms, they contain their own genome as well as an independent and fully functional endogenous protein biosynthesis machinery. However, the coding capacity of the mitochondrial genome is restricted to a few polypeptides, i.e., eight in the baker`s yeast Saccharomyces cerevisiae and thirteen in the human genome. Hence, most mitochondrial proteins – recent proteomic studies predict a total number of at least 500-800 different polypeptides – are encoded in the nuclear genome and have to be synthesized as precursors at cytosolic ribosomes. In this review mitochondrial protein import in fungi and animals is discussed.

Glossary

Chaperone:

Proteins that prevent irregular interactions of their substrate polypeptides based on the nonspecific binding to exposed hydrophobic segments. In many cases, substrate affinity of chaperones is regulated by nucleotide binding.

Import motor or PAM (presequence translocase-associated motor):

ATP-consuming translocation system attached to the inner face of the inner mitochondrial membrane with the core component mtHsp70 that drives import of precursor proteins into the matrix compartment.

MCF (metabolite carrier family):

Family of strongly hydrophobic proteins integrated into the inner mitochondrial membrane that confer exchange of metabolites between the cytosol and the mitochondrial matrix compartment.

MIA (mitochondrial intermembrane space import and assembly):

Disulfide-relay system in the intermembrane space that mediates the import and folding of cysteine-rich precursor proteins in the intermembrane space.

Peptidyl-prolyl cis-trans isomerase:

Enzyme that catalyzes the cis-trans isomeration of peptide bonds involving the amino acid proline.

Processing:

Specific removal of N-terminal targeting sequences during the mitochondria import process by specific endoproteases.

Receptor:

Protein integrated into the mitochondrial outer membrane that interacts specifically with polypeptides containing mitochondrial targeting signals, thereby initiating the import process.

SAM/TOB (sorting and assembly machinery/topogenesis of β-barrel proteins):

Multi-subunit protein complex that mediates the insertion and assembly of (mainly) β-barrel precursor proteins into the outer mitochondrial membrane.

TIM22 (translocase of the inner mitochondrial membrane with 22-kDa-core protein):

Multi-subunit protein complex that mediates the insertion of (mainly polytopic) mitochondrial precursor proteins into the inner mitochondrial membrane in dependency of the electric potential Δψ across the inner membrane.

TIM23 (translocase of the inner mitochondrial membrane with 23-kDa-core protein; also termed presequence translocase):

Multi-subunit protein complex that mediates the translocation of mitochondrial precursor proteins across or into the inner mitochondrial membrane in dependency of the electric potential Δψ across the inner membrane. For matrix import, TIM23 cooperates with PAM.

TPR (tetratricopeptide repeat) motif:

Degenerate protein sequence of approximately 34 amino acids containing the consensus residues -W-LG-Y-A-F-A-P-. The sequence occurs in tandem arrays that arrange into a highly conserved tertiary structure. Acts as protein-protein interaction module.

Translocase complex:

Membrane-integrated multi-subunit protein complex that mediates the translocation of mitochondrial precursor proteins across the respective mitochondrial membrane.