Figure 1 | Protein-import pathways for mitochondrial proteins.   Precursor proteins (brown) with positively charged amino-terminal presequences, -barrel outer-membrane proteins (dark green), and multispanning inner-membrane proteins (blue) with internal targeting signals are recognized by specific receptors of the translocase of the outer mitochondrial membrane (TOM) — that is, by Tom20, Tom22 and/or Tom70. Up to three dimers of Tom70 are recruited per precursor (each Tom70 structure shown here represents a dimer). The precursor proteins are then translocated through the Tom40 pore (the small Tom proteins of the TOM complex — Tom5, Tom6 and Tom7 — are not shown). The TOM complex contains two or three pores. The -barrel proteins then require the small Tim proteins (Tim9–Tim10) to guide them through the intermembrane space, and the sorting and assembly machinery (SAM complex) for insertion and assembly into the outer membrane. Outer-membrane proteins with single transmembrane spans can be directly inserted into the outer membrane by the TOM complex. Presequence-containing preproteins use the presequence translocase of the inner mitochondrial membrane (the TIM23 complex) for transport across the inner membrane. Tim23 forms a pore in the inner membrane. Presequence-containing inner membrane proteins can either be directly inserted into the inner membrane by the presequence translocase or be translocated to the matrix side and exported into the inner membrane¹⁰⁷. It has been reported that the extreme amino terminus of Tim23 spans the outer membrane³⁶ (not shown). The membrane potential () and the function of the presequence-translocase-associated import-motor (PAM) complex are essential for the translocation of presequence-containing proteins into the matrix. Mitochondrial heat-shock protein-70 (mtHsp70) is the central motor component. It cooperates with Tim44, Pam16 and Pam18 at the inner membrane and requires the matrix protein Mge1 (mitochondrial GrpE-related protein-1) for nucleotide exchange. In the matrix, the mitochondrial processing peptidase (MPP) cleaves off the presequence. Multispanning inner-membrane proteins with internal signals require the Tim9–Tim10 complex for transport across the outer membrane and the intermembrane space. The insertion of these proteins into the inner membrane is catalysed by the twin-pore carrier translocase of the inner mitochondrial membrane (the TIM22 complex), which uses the membrane potential as an external driving force. This translocase contains two pores.

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