Versatility of the mitochondrial protein import machinery

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Abstract
Mitochondria comprise 15–20% of the proteins of a cell. Only very few mitochondrial proteins are synthesized inside the organelle. Over 98% of mitochondrial proteins are made as preproteins in the cytosol. The typical mitochondrial preproteins contain amino-terminal signal sequences (presequences) that are removed after import into the organelle. A large second class of hydrophobic preproteins do not carry cleavable presequences, but several internal signals. The translocase of the outer mitochondrial membrane (TOM) contains receptors and a general import pore (GIP). Presequence-containing preproteins are recognized by the receptors Tom20 and Tom22, whereas preproteins with internal signals are preferentially recognized by Tom70. All preproteins are imported by the same GIP formed by the channel protein Tom40. The mitochondrial inner membrane contains two distinct translocases. Presequence-containing preproteins are directed into the TIM23 complex in a membrane potential-dependent manner. Matrix Hsp70 interacts with the TIM23 complex through Tim44 and functions as ATP-dependent motor to drive import of the preproteins into the matrix. The second pathway into the inner membrane is used by hydrophobic preproteins with several internal signals. They are guided through the intermembrane space by tiny Tim proteins (Tim9–Tim10) and dock to the membrane-integrated TIM22 complex. In a membrane potential-dependent manner, the preproteins are inserted into the TIM22 complex and are probably laterally released into the inner membrane. Several variations in these pathways exist for special preproteins. Preproteins carrying additional sorting signals can diverge from the main pathways at distinct stages and are sorted to mitochondrial subcompartments.

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