Mitochondrial Precursor Proteins

Most precursors are targeted to the mitochondria by a cleavable N-terminal amphipathic signal sequence called the presequence. Precursors targeted to the mitochondrial membranes or intermembrane space contain additional non-cleavable internal import signals.

Cytosolic chaperone and co-chaperone complexes use energy from ATP hydrolysis to bind and stabilize the unfolded precursors. This keeps them in a disaggregated state before the complexes can transport them to the translocons on the mitochondrial membranes.

Import receptors on the mitochondrial membrane can recognize both presequences and import signals to allow the unfolded peptides to thread through the TOM-TIM complexes.

Proteins targeted to the mitochondrial membranes contain internal hydrophobic stop-transfer signal sequences that arrest their translocation. Once the presequence is cleaved by mitochondrial processing peptidases these proteins are pulled into the intermembrane space and directly inserted into the inner membrane, using the hydrophobic sequence as an anchor.

For proteins targeted to the intermembrane space, inner membrane proteases cleave the presequence as the chaperones help the processed precursors fold into their native conformation.

Proteins containing matrix-targeting sequences are cleaved by matrix proteases and the processed peptide is folded and released as a functional protein.