Abstract
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase.
Highlights
The mitochondrial inner membrane separates two aqueous compartments, the matrix and the intermembrane space, that differ in their protein and metabolite composition and host distinct metabolic pathways
Most mitochondrial metabolite carriers belong to the mitochondrial carrier family (MCF, in humans SLC25 for solute carrier family 25)
ATP binding to Hsp70 triggers substrate release from Hsp70, the carrier precursor is handed over to the central receptor Tom22, and individual helix-loop-helix modules are threaded into the Tom40 pore in a hairpin-like conformation [21,62]. It is currently unclear how mitochondrial pyruvate carrier precursors with their distinct topology are handled by the the outer membrane (TOM) complex, it is tempting to speculate that at least the two C-terminal TM segments of Mpc2/Mpc3 may be recognized in a fashion similar to classical carriers
Summary
The mitochondrial inner membrane separates two aqueous compartments, the matrix and the intermembrane space, that differ in their protein and metabolite composition and host distinct metabolic pathways. The best studied carrier is the ADP/ATP threeAAC homologous repeats consisting of twonucleotide transmembrane segmentsthat each They uniformly possess carrier (yeast)/ANT (human; adenine translocator) has been employed both as six transmembrane segments and expose both their N- and C-termini to the intermembrane space a model substrate to study carrier biogenesis and for the analysis of MCF structure and transport (Figure 2) [4,12,17,19,24]. Recent studies indicate that the sideroflexins, with five transmembrane segments to dimers, forming a six TM functional unit like the SWEETs. MPC subunits MPC2 (mammals) as and the N-terminus in the intermembrane space (IMS), depend on the TIM22 carrier pathway well as Mpc and Mpc (yeast) have three TM segments (Figure 2). The mitochondrial pyruvate carrier components and the sideroflexins with their unique topologies have challenged long-held views of the structural requirements for TIM22 substrates
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