Trends in Biochemical Sciences
OpinionMitochondrial protein import: from transport pathways to an integrated network
Section snippets
Two classical import routes for mitochondrial proteins
Mitochondria are the powerhouses of eukaryotic cells and play important roles in cellular metabolism and regulation. They consist of two membranes, an intermembrane space and an inner compartment, the matrix. Although mitochondria contain a complete genetic and protein synthesis system in the matrix, derived from their prokaryotic ancestor, ∼99% of mitochondrial proteins are encoded in the nucleus of the cell and are synthesized as precursors in the cytosol 1, 2, 3, 4. The precursor proteins
Identification of new import components and pathways
In 2002, the new subunit Tim50 of the presequence translocase (TIM23 complex) was identified. Tim50 is essential for the presequence pathway and for viability of cells, which indicates that it is a major player in mitochondrial biogenesis 7, 8. Later, numerous new mitochondrial import components were identified. For example, important regulatory subunits that function in the TIM23 complex, the motor PAM or in preprotein processing were identified for the presequence pathway (Figure 1) 9, 11, 14
Two pathways for protein insertion into the mitochondrial outer membrane
The mitochondrial outer membrane contains two classes of proteins: β-barrel proteins, which are integrated into the membrane by multiple β-strands and are derived from the bacterial ancestor of mitochondria, and proteins with α-helical transmembrane segments, which probably derive from the eukaryotic host cell. Although the TOM complex is the main entry gate for the large majority of mitochondrial precursor proteins, further machineries are needed to insert proteins into the outer membrane.
In
Redox-regulated protein import into the intermembrane space
A few intermembrane space proteins are imported via the presequence pathway. The preproteins are laterally released from the TIM23 complex, and the mature proteins are cleaved off by an intermembrane space-exposed peptidase (Figure 1). However, the majority of intermembrane space proteins use the MIA pathway, during which the Mia40 protein interacts with the precursor proteins via disulfide bonds 21, 23. Many intermembrane space proteins contain characteristic cysteine motifs, and the mature
Integration of protein import machineries into a network of organellar and cellular functions
In addition to discovering new protein import routes into mitochondria, recent studies suggested unexpected connections of the preprotein translocases to various other mitochondrial systems. In this section, we summarize these observations and then propose a hypothesis on the organization of the protein import system.
Regarding the presequence pathway, the TIM23 complex is physically connected to the mitochondrial respiratory chain (Figure 1) 54, 55, 56. Tim21 binds to a supercomplex formed by
Concluding remarks
The analysis of mitochondrial protein import has provided exciting new insights into a highly complex system of organellar biogenesis and function. However, many more unexpected findings can be anticipated, as many open questions remain (Box 2). We speculate that further import pathways may exist; for example, some small proteins of the inner membrane are imported without a clear requirement for a membrane potential Δψ [78], whereas a Δψ is strictly needed for the two known translocases of the
Acknowledgments
This work has been supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 746, Excellence Initiative of the German Federal & State Governments (EXC 294), Gottfried Wilhelm Leibniz Program, Landesforschungspreis Baden-Württemberg, and Bundesministerium für Bildung und Forschung.
Glossary
- ERMES
- The ER-mitochondria encounter structure (ERMES) tethers the endoplasmic reticulum (ER) to the outer membrane of mitochondria. This complex consists of the ER-localized protein Mmm1 and the mitochondria-bound proteins Mdm10, Mdm12, Mdm34 and Gem1.
- MIA
- The mitochondrial intermembrane space import and assembly (MIA) machinery mediates oxidative protein transport and folding. Mia40 cooperates with the sulfhydryl oxidase Erv1 in a disulfide relay to drive the import of cysteine-rich proteins into
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