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Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.

Generally, polypeptides are unfolded by two distinct mechanisms before being transported in the TOM/TIM import pathway: spontaneous global unfolding and catalyzed unfolding. Precursors with shorter presequences undergo spontaneous global unfolding. In contrast, precursors with longer positively charged presequences undergo local unfolding. The unstructured presequence then traverses the TOM/TIM import complexes and interacts with the inner membrane’s negative charges to reach the matrix. Mitochondrial Hsp70 (mtHsp70) associated with TIM44 recognizes the emerging polypeptide and translocates it entirely into the matrix by accelerating the unfolding process. mtHsp70 also traps any incoming loosely folded precursors without undergoing any conformational change and translocates them to the matrix without undergoing any conformational change.

In contrast, the translocation of tightly folded polypeptides induces ATP-dependent conformational changes in mtHsp70. mtHsp70 utilizes the ATP hydrolysis energy to pull the incoming peptide across the TIM translocase. Rebinding of ATP causes the opening of mtHsp70, and the precursor gets released into the matrix.

Two models can describe precursor translocation by the mtHsp70: the thermal ratchet model and the cross-bridge ratchet model. MtHsp70 translocates precursors by trap and release mechanism in the thermal ratchet model. mtHsp70 uses the ATP hydrolysis energy to bind the spontaneously unfolded precursors and trap them into the matrix, preventing further backward movement. In contrast, translocation by cross-bridge ratchet mechanism involves precursor unfolding coupled to an ATP-dependent conformational change of mtHsp70. mtHsp70 generates an ATP-dependent pulling force to transport precursors into the matrix. Accelerated precursor unfolding facilitates its unidirectional forward movement and transport into the matrix.

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