FIGURE 1: Overview of the main mitochondrial protein import pathways. The majority of mitochondrial proteins are synthesized as precursors on free ribosomes in the cytosol (1). Precursors are guided by cytosolic chaperones to the main entry gate of mitochondria, the TOM complex (2). Precursors destined to the matrix pass through the TOM (2) and TIM23 (3) translocases and require the membrane potential ∆ψ. Import into the matrix is facilitated by the Hsp70 containing motor complex PAM that hydrolyzes ATP (4). Precursors of single spanning inner membrane proteins cross the mitochondrial outer membrane through the TOM complex (2) and are laterally released into the mitochondrial inner membrane by the TIM23 machinery (3 and 5). Precursors of outer membrane β-barrel proteins also use the TOM complex (2). In the intermembrane space (IMS) they are delivered to the sorting and assembly machinery SAM with the help of small Tim chaperones (6 and 7) from where they are subsequently inserted into the outer membrane. Precursors of metabolite carriers cross the outer membrane via TOM (2) and are guided by small Tim chaperones (6) to the TIM22 translocase (8) that facilitates their insertion into the inner membrane (9). Many precursors destined to the intermembrane space utilize the TOM complex (2) and the MIA machinery (10). Precursors of α-helical outer membrane proteins associate with the Tom70 receptor and are subsequently inserted into the mitochondrial outer membrane and typically depend on the MIM machinery (11).