Protein Transport into the Inner Mitochondrial Membrane

Translocation across the inner membrane is driven by the electrochemical potential of the proton gradient across the inner membrane.

Negative charges towards the matrix side of the inner membrane unfold the precursor and pull the positively charged presequence in.

Two distinct translocases, TIM23 and TIM22, facilitate the transport of separate classes of proteins across the inner membrane.

Translocation across the TIM22/23 complex follows two distinct routes: the conservative pathway and the stop-transfer pathway.

In the conservative pathway, precursors containing N-terminal matrix targeting sequences are first transported to the matrix and then exported to the inner membrane for insertion.

Transmembrane insertion machinery called the OXA complex associates with precursors, preventing peptide aggregation and facilitating spontaneous integration into the inner membrane.

In the stop-transfer pathway, additional internal hydrophobic sequences block the precursor's translocation across the TIM channel.

The matrix Hsp70 pulls the remaining N-terminal end of the protein  as the TIM complex releases the proteins laterally into the inner membrane. The hydrophobic stop-transfer sequences form the transmembrane segment and function to anchor the protein onto the inner membrane.