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.