Peroxisomal proliferator activated receptor agonists as potential therapy for mitochondrial respiratory chain complex (RCC) defects

display slow growth, decreased mitochondrial membrane potential, and impaired respiratory capacity. These defects are reversed upon restoration of fusion capability. The importance of mitochondrial fusion is further underscored by the fact that two neurodegenerative diseases, Charcot– Marie–Tooth disease type 2A (CMT) and autosomal dominant optic atrophy (DOA), are caused by mutations in Mfn2 and OPA1, respectively.To further explore the physiological requirements for mitochondrial fusion, we have created conditional knockout mice for both Mfn1 and Mfn2. Interestingly, Mfn2 is required for proper cerebellar development. When cerebellar primordia is targeted embryonically, pups display severe problems in balance and motility, resulting in feeding problems and death by about two weeks of age. When Purkinje cells, the only efferent processes of the cerebellum, are targeted upon maturity, they actually degenerate, causing the mice to develop tremors and wobble while walking. Thus, mitochondrial fusion is required in the central nervous system along with the peripheral motor neurons and optic nerve affected in CMT and DOA.Disruption of both Mfn1 and Mfn2 in skeletal muscle results in severely runted mice, which die at around two months of age. Muscle mass is greatly reduced in these mice, and cross-sectional analysis reveals significantly decreased muscle fiber widths. A modified Gomori-trichrome stain results in predominantly red fibers. In addition, a succinate-dehydrogenase (SDH) enzymatic assay reveals greatly increased activity in all fibers. The combination of red fibers and increased SDH activity is a hallmark of many mitochondrial diseases, suggesting a common link between deficiencies in mitochondrial fusion and traditional mitochondrial diseases.