CMT 2A: Mitochondrial Fusion Protects against Neurodegeneration in the Cerebellu

[Guest guest]

Mitochondrial Fusion Protects against Neurodegeneration in the

Cerebellum.

Chen H, McCaffery JM, Chan DC.

Division of Biology, California Institute of Technology, Pasadena,

CA 91125, USA.

Mutations in the mitochondrial fusion gene Mfn2 cause the human

neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the

cellular basis underlying this relationship is poorly understood. By

removing Mfn2 from the cerebellum, we established a model for

neurodegeneration caused by loss of mitochondrial fusion.

During development and after maturity, Purkinje cells require Mfn2

but not Mfn1 for dendritic outgrowth, spine formation, and cell

survival. In vivo, cell culture, and electron microscopy studies

indicate that mutant Purkinje cells have aberrant mitochondrial

distribution, ultrastructure, and electron transport chain activity.

In fibroblasts lacking mitochondrial fusion, the majority of

mitochondria lack mitochondrial DNA nucleoids. This deficiency

provides a molecular mechanism for the dependence of respiratory

activity on mitochondrial fusion. Our results show that exchange of

mitochondrial contents is important for mitochondrial function as

well as organelle distribution in neurons and have important

implications for understanding the mechanisms of neurodegeneration

due to perturbations in mitochondrial fusion.