Mitochondria contain many proteins. Thirteen polypeptides (mostly membrane components of the electron transport chain) are encoded by the mitochondrial (mt) genome and synthesized in that organelle using its own protein-synthesizing system. However, the vast majority (at least several hundreds) are encoded by nuclear genes, and synthesized outside the mitochondria on cytosolic polyribosomes, and must be imported. Most progress has been made in the study of proteins present in the mitochondrial matrix, such as the ATP synthase sub units. Only the pathway of import of matrix proteins will be discussed in any detail here.

Matrix proteins must pass from cytosolic polyribosomes through the outer and inner mitochondrial membranes to reach their destination. Passage through the two membranes is called translocation. They have an amino terminal leader sequence (presequence), about 20 to 50 amino acids in length, which is amphipathic and contains many hydrophobic and positively charged amino acids (eg, Lys or Arg). The presequence is equivalent to a signal peptide mediating attachment of polyribosomes to membranes of the ER (see later), but in this instance it targets proteins to the matrix. Some general features of the passage of a protein from the cytosol to the mitochondrial matrix are shown in Figure 1.

Fig1. Entry of a protein into the mitochondrial matrix.After synthesis on cytosolic polyribosomes, an unfolded protein contain ing a matrix-targeting sequence interacts with the cytosolic chaperone Hsp70 and then with mitochondria (mt) via the receptor translocase of the outer membrane (Tom) 20/22. Transfer to the import channel Tom 40 followed by translocation across the outer membrane is the next step. Transport across the inner mt membrane occurs via a complex comprising Tim (translocase of the inner membrane) 23 and Tim 17 proteins. On the inside of the inner mt membrane, the protein interacts with the matrix chaperone Hsp 70, which in turn interacts with membrane protein Tim 44. The hydrolysis of ATP by mt Hsp70 probably helps drive the translocation, as does the electronegative interior of the matrix. The targeting sequence is subsequently cleaved by the matrix protease, and the imported protein assumes its final shape, sometimes with the prior aid of interaction with an mt chaperonin. At the site of translocation, the outer and inner mt membranes are in close contact. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane.

Translocation occurs posttranslationally, after the matrix preproteins are released from the cytosolic polyribosomes. Interactions with a number of cytosolic proteins that act as chaperones and as targeting factors occur prior to translocation.

Two distinct translocation complexes are situated in the outer and inner mitochondrial membranes, referred to (respectively) as translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM). Each complex has been analyzed and found to be composed of a number of proteins, some of which act as receptors (eg, Tom20/22) for the incoming proteins and others as components (eg, Tom40) of the transmembrane pores through which these proteins must pass. Proteins must be in the unfolded state to pass through the complexes, and this is made possible by ATP dependent binding to several chaperone proteins including Hsp70 (see Figure 49–3). In mitochondria, chaperones are involved in translocation, sorting, folding, assembly, and degradation of imported proteins. A proton-motive force across the inner membrane is required for import; it is made up of the electric potential across the membrane (inside negative) and the pH gradient (see Chapter 13). The positively charged leader sequence may be helped through the membrane by the negative charge in the matrix. In addition, close apposition at contact sites between the outer and inner membranes is necessary for translocation to occur.

The presequence is split off in the matrix by a matrix protease. Contact with other chaperones present in the matrix is essential to complete the overall process of import. Interaction with mt-Hsp70 (mt = mitochondrial; Hsp = heat shock protein; 70 = ~70 kDa) ensures proper import into the matrix and prevents misfolding or aggregation, while inter action with the mt-Hsp60–Hsp10 system ensures proper folding. The interactions of imported proteins with the above chaperones require hydrolysis of ATP to drive them.

The above describes the major pathway of proteins des tined for the mitochondrial matrix. However, certain proteins insert into the outer mitochondrial membrane facilitated by the TOM complex. Others remain in the intermembrane space, and some insert into the inner membrane. Yet others proceed into the matrix and then return to the inner membrane or intermembrane space. A number of proteins contain two signaling sequences—one to enter the mitochondrial matrix and the other to mediate subsequent relocation (eg, into the inner membrane). Certain mitochondrial proteins do not contain presequences (eg, cytochrome c, which locates in the inter membrane space), and others contain internal presequences. Overall, proteins employ a variety of mechanisms and routes to attain their final destinations in mitochondria.

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