Mechanisms of protein sorting in mitochondria - PubMed (original) (raw)
Review
Mechanisms of protein sorting in mitochondria
Diana Stojanovski et al. Cold Spring Harb Perspect Biol. 2012.
Abstract
A protein's function is intimately linked to its correct subcellular location, yet the machinery required for protein synthesis is predominately cytosolic. How proteins are trafficked through the confines of the cell and integrated into the appropriate cellular compartments has puzzled and intrigued researchers for decades. Indeed, studies exploring this premise revealed elaborate cellular protein translocation and sorting systems, which ensure that all proteins are shuttled to the appropriate cellular destination, where they fulfill their specific functions. This holds true for mitochondria, where sophisticated molecular machines serve to recognize incoming precursor proteins and integrate them into the functional framework of the organelle. We summarize the recent progress in our understanding of mitochondrial protein sorting and the machineries and mechanisms that mediate and regulate this highly dynamic cellular process essential for survival of virtually all eukaryotic cells.
Figures
Figure 1.
Overview of mitochondrial protein sorting pathways. Cytosolic chaperones deliver precursor proteins to the organelle in a translocation-competent state. Some α-helical proteins are inserted into the outer membrane with the help of Mim1. Virtually all other precursors initially traverse the outer membrane via the TOM complex and are subsequently routed to downstream sorting pathways. Biogenesis of outer membrane β-barrel proteins requires the small TIM chaperones of the IMS and the SAM complex. Cysteine-containing IMS proteins are imported via the MIA pathway. Metabolite carriers of the inner mitochondrial membrane are transferred by the small TIM chaperones to the TIM22 complex, which mediates their membrane integration. Presequence-containing precursors are directly taken over from the TOM complex by the TIM23 machinery that either inserts these proteins into the membrane or translocates them into the matrix in cooperation with the import motor PAM. OM, outer membrane; IMS, intermembrane space; IM, inner membrane, Δψ, membrane potential across the inner mitochondrial membrane.
Figure 2.
Biogenesis of outer membrane proteins. (A) Several mitochondrial outer membrane proteins are characterized by a β-barrel topology. On passage of the TOM complex, β-barrel precursors are guided through the aqueous IMS by hexameric small TIM complexes to the SAM complex. A specific import signal (β-signal), which is located within the last β-strand of the precursor, is recognized by the Sam35 receptor. Sam50 forms a central cavity in the SAM complex, where membrane insertion and folding of precursors takes place. (B) Multiple pathways mediate the insertion of α-helical proteins into the outer membrane. Signal-anchored precursors require Mim1 for membrane integration (left). The biogenesis of Tom22, which contains a single central transmembrane segment, depends on both the TOM and SAM–Mdm10 complexes (middle). Polytopic α-helical outer membrane proteins are recognized by the Tom70 receptor and transferred to Mim1 for membrane insertion (right). OM, outer membrane; IMS, intermembrane space; red arrow, β-strand; yellow arrow, β-signal; blue bar, transmembrane α-helix C, carboxy; N, amino.
Figure 3.
Import of cysteine-containing precursor proteins into the IMS. The Mia40 receptor forms transient intermolecular disulfide bonds with precursors emerging from the TOM complex. Mia40 functions not only as a receptor, but also as an oxidoreductase by catalyzing the formation of intramolecular disulfide bonds within the precursor together with the sulfhydryl oxidase Erv1. A ternary complex of Mia40, Erv1, and a bound precursor protein allows for the incorporation of multiple disulfide bonds. Erv1 re-oxidizes Mia40 for another round of import and transfers electrons via cytochrome c (Cyt.c) and cytochrome c oxidase (COX) to molecular oxygen. OM, outer membrane; IMS, intermembrane space; IM, inner membrane.
Figure 4.
Insertion of metabolite carriers into the inner mitochondrial membrane. The Tom70 receptor takes over metabolite carrier precursors from cytosolic chaperones. The precursors pass the outer membrane in a loop conformation. In the IMS, the hydrophobic transmembrane segments of carriers are shielded by the Tim9/Tim10 chaperone complex, which delivers the precursor to the TIM22 machinery in the inner membrane. Tim54 and the adaptor protein Tim12 transfer the precursor to the protein-conducting channel formed by Tim22. Tim18, and Sdh3 are required for assembly and stability of the translocase. The membrane potential across the inner mitochondrial membrane (Δψ) drives the insertion of metabolite carriers, which finally adopt their functional, dimeric state. OM, outer membrane; IMS, intermembrane space; IM, inner membrane.
Figure 5.
Import of presequence-containing precursor proteins (preproteins) into the inner membrane and matrix. Amino-terminal positively charged presequences are preferentially recognized by the Tom20 receptor on the mitochondrial surface. On the trans side of the protein-conducting Tom40 channel, presequences are bound by the IMS domain of Tom22. Membrane potential (Δψ)-dependent transfer of preproteins to the TIM23 machinery in the inner membrane involves Tim50 and Tim21. Preproteins with a hydrophobic stop-transfer signal (blue bar) are directly released from the protein-conducting channel formed by Tim23 into the inner membrane. This Δψ-dependent process is supported by the Tim21-dependent coupling of respiratory chain supercomplexes to TIM23. Stepwise translocation of soluble preproteins into the matrix requires the dynamic coupling of the ATP-driven mtHsp70-containing import motor, which leads to a loss of Tim21 from the TIM23 complex. Finally, the matrix processing peptidase (MPP) proteolytically removes presequences from both inner membrane and matrix preproteins. OM, outer membrane; IMS, intermembrane space; IM, inner membrane; _bc_1, cytochrome _bc_1 complex (complex III); COX, cytochrome c oxidase (complex IV).
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References
- Abe Y, Shodai T, Muto T, Mihara K, Torii H, Nishikawa S, Endo T, Kohda D 2000. Structural basis of presequence recognition by the mitochondrial protein import receptor Tom20. Cell 100: 551–560 - PubMed
- Alder NN, Jensen RE, Johnson AE 2008. Fluorescence mapping of mitochondrial TIM23 complex reveals a water-facing, substrate-interacting helix surface. Cell 134: 439–450 - PubMed
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