Mitochondrial dynamics and neurodegeneration

Human genetic studies indicate that defects in mitochondrial dynamics lead to neurodegenerative disease. Charcot‐Marie‐Tooth disease type 2A (CMT2A) is caused by mutations in the mitofusin Mfn2. Mitofusins are mitochondrial outer membrane proteins essential for mitochondrial fusion. Dominant optic atrophy is caused by mutations in OPA1, a mitochondrial inner membrane protein also essential for mitochondrial fusion. We have used mouse models to understand how mutations in Mfn2 affect mitochondrial fusion, and how such defects lead to neurodegeneration. Using mice with a conditional null allele of Mfn2, we show that loss of Mfn2 leads to several cerebellar dysfunction. Our results indicate that mitochondrial fusion is required for the development and maintenance of specific neurons. In addition, using knock‐in mouse models of CMT2A, we have gained insight into how Mfn1 cooperates with Mfn2 to mediate mitochondrial fusion.