Distribution of mitochondrial fusion proteins inside mitochondria and related human diseases resulting from defects in gene expression or protein function (a). Mitofusin 2 (MFN2) and optic atrophy protein 3 (OPA3) are present in the outer mitochondrial membrane; dynamin-related protein optic atrophy 1 (OPA1) is localized in the intermembrane space and is tethered to the inner mitochondrial membrane. The top right of the figure illustrates the molecular pathway responsible for mitophagy: PTEN-induced putative kinase protein 1 (PINK1) phosphorylates Parkin, an ubiquitin E3 ligase that targets several outer membrane proteins including mitofusin. Ubiquitination of MFN2 in damaged mitochondria starts the mitophagic process. ADOA: autosomal dominant optic atrophy; ADOAC: autosomal dominant optic atrophy and cataract; HR: heptad repeat; PD: Parkinson’s disease. Below (b), schematics of functional domains of the mitochondrial fusion proteins (HR: heptad repeat domain; TM: transmembrane domain; PR: proline-rich domain; MIS: mitochondrial import sequence; GED: GTPase effector domain; Mss: mitochondrial signal sequence).