Mitochondrial fusion proteins and human diseases

Abstract

Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

Figure 1

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).