Cooperation of TOM and TIM23 Complexes during Translocation of Proteins into Mitochondria

• TOM and TIM23 complexes cooperate during translocation of proteins into mitochondria.
• Tim50, through its C-terminal segment, interacts with Tom22.
• Tim50–Tom22 interaction is independent of other TOM–TIM23 contacts.
• Exposure of Tim23 on the mitochondrial surface is dependent on the TOM complex.
• Intricate protein interaction network is required for TOM–TIM23 cooperation.

Translocation of the majority of mitochondrial proteins from the cytosol into mitochondria requires the cooperation of TOM and TIM23 complexes in the outer and inner mitochondrial membranes. The molecular mechanisms underlying this cooperation remain largely unknown. Here, we present biochemical and genetic evidence that at least two contacts from the side of the TIM23 complex play an important role in TOM–TIM23 cooperation in vivo. Tim50, likely through its very C-terminal segment, interacts with Tom22. This interaction is stimulated by translocating proteins and is independent of any other TOM–TIM23 contact known so far. Furthermore, the exposure of Tim23 on the mitochondrial surface depends not only on its interaction with Tim50 but also on the dynamics of the TOM complex. Destabilization of the individual contacts reduces the efficiency of import of proteins into mitochondria and destabilization of both contacts simultaneously is not tolerated by yeast cells. We conclude that an intricate and coordinated network of protein–protein interactions involving primarily Tim50 and also Tim23 is required for efficient translocation of proteins across both mitochondrial membranes.

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