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Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death. Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.

Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors contain a cleavable 15 to 50 amino acid-long N-terminal presequence and a non-cleavable hydrophobic internal import signal. Cytosolic chaperones and co-chaperones such as Hsp90/p23 and Hsc70/Hsp40 guide these precursors to the translocase of the outer mitochondrial membrane or the TOM complex. TOM complex is the first point of contact for importing all mitochondrial precursors. Mitochondrial presequences are usually identified by TOM20 receptors, while TOM70 receptors recognize precursors with internal import signals. After initial recognition, the precursors are transferred to the central TOM22 receptor. The intermembrane space domain of the TOM22 receptor functions as a binding site for the precursor emerging out of the TOM complex. Positively-charged presequences induce the opening of the TOM40 voltage-gated channel and pass into the intermembrane space. Upon entering the intermembrane space, precursors are transferred to the translocase of the inner membrane or TIM complex for further translocation into the internal subcompartments. Precursors containing presequences are translocated across the inner membrane through the TIM23 channel, while the TIM22 channel translocates precursors with internal import signals. Depending on the destination of the precursor, the following five major mitochondrial import pathways are identified.

The presequence pathway transports precursor with cleavable N terminal presequences translocating through the TOM40 and TIM23 channels into the matrix. Presequence translocase associated motor (PAM) uses the energy of ATP hydrolysis and transports the complete peptide into the matrix space. Inside the matrix, presequence is cleaved by matrix processing peptidases, and the processed precursor is then folded to an active protein.

In contrast, precursors with non-cleavable presequence and internal import signals are translocated by the carrier pathway, beta-barrel pathway, MIA pathway, or the Mitochondrial import or MIM pathway. In the carrier pathway, inner membrane carrier proteins are translocated by the TOM complex on the outer membrane and carrier translocases, TIM22, on the inner membrane. In the beta-barrel pathway, precursors are translocated through the TOM complex and then integrated onto the outer membrane by the sorting and assembly machinery (SAM) complex. Some cysteine-rich proteins targetted to the intermembrane space (IMS) are transported by a fourth pathway involving the TOM complex and a mitochondrial import and assembly machinery (MIA) complex that helps pull the precursor across the TOM channel into the intermembrane space. Finally, the MIM pathway translocates and integrates multipass outer membrane proteins with alpha-helical transmembrane segments and precursors with N terminal hydrophobic anchor signals.

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