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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.

Sorting of outer membrane proteins:

Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast, alpha-helical membrane-anchored proteins are translocated by the TOM complex and inserted by the mitochondrial import complex.

Sorting of intermembrane space proteins:

Intermembrane space proteins are sorted via the mitochondrial intermembrane space import and assembly machinery or (MIA) pathway. MIA40 is an oxidoreductase of the intermembrane space (IMS) that recognizes and binds specific cysteine residues upstream or downstream of the hydrophobic intermembrane space sorting sequence called the MISS/ITS signal. MIA40 contains a redox-active CPC motif that facilitates thiol-disulfide exchange with the cysteine residues of the incoming precursor. Dimeric flavin-dependent oxidoreductase called Erv1 cooperates with MIA40 in oxidizing the precursor cysteine residues, thereby folding and transporting the oxidized precursor into the IMS. Erv1 then transfers electrons to the reduced CPC motif of MIA40 via cytochrome C and cytochrome C oxidase or respiratory chain IV of the electron transport chain. Oxidized Mia40 gets ready for another round of IMS precursor import.

Sorting of inner membrane and matrix proteins:

Inner membrane proteins with cleavable N terminal presequences are translocated through the presequence translocase TIM23 assisted by the ATP-dependent presequence translocase associated motor (PAM). In contrast, inner membrane proteins with internal import signals called carrier signatures are translocated via the carrier translocase TIM22. Translocation across TIM23 or TIM22 to the inner membrane can follow two distinct routes of sorting: the conservative and stop transport pathways. In the stop-transfer pathway, the movement of precursors with internal hydrophobic patches gets blocked across the TIM22/23 channel, which gets laterally released onto the inner membrane. In the conservative pathway, precursors are first translocated to the matrix and then assembled into the inner membrane by the Oxa protein. However, precursors targeted to the matrix are cleaved by matrix processing peptidases. Some precursors are further processed by mitochondrial intermediate peptidase or inner membrane protease I depending on additional presequence cleavage sites. Processed matrix proteins are then released into the matrix to be folded by chaperonins using ATP hydrolysis energy.

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