Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons.
Mitochondrial dysfunction is implicated in aging and degenerative disorders such as Parkinson's disease (PD). Continuous fission and fusion of mitochondria shapes their morphology and is essential to maintain oxidative phosphorylation. Loss-of-function mutations in PTEN-induced kinase1 (PINK1) or Parkin cause a recessive form of PD and have been linked to altered regulation of mitochondrial dynamics. More specifically, the E3 ubiquitin ligase Parkin has been shown to directly regulate the levels of mitofusin 1 (Mfn1) and Mfn2, two homologous outer membrane large GTPases that govern mitochondrial fusion, but it is not known whether this is of relevance for disease pathophysiology. Here, we address the importance of Mfn1 and Mfn2 in midbrain dopamine (DA) neurons in vivo by characterizing mice with DA neuron-specific knockout of Mfn1 or Mfn2. We find that Mfn1 is dispensable for DA neuron survival and motor function. In contrast, Mfn2 DA neuron-specific knockouts develop a fatal phenotype with reduced weight, locomotor disturbances and death by 7 weeks of age. Mfn2 knockout DA neurons have spherical and enlarged mitochondria with abnormal cristae and impaired respiratory chain function. Parkin does not translocate to these defective mitochondria. Surprisingly, Mfn2 DA neuron-specific knockout mice have normal numbers of midbrain DA neurons, whereas there is a severe loss of DA nerve terminals in the striatum, accompanied by depletion of striatal DA levels. These results show that Mfn2, but not Mfn1, is required for axonal projections of DA neurons in vivo.
Department of Laboratory Medicine, and 2Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm, Sweden.
Seungmin
S
Lee
Fredrik H
FH
Sterky
Arnaud
A
Mourier
Mügen
M
Terzioglu
Staffan
S
Cullheim
Lars
L
Olson
Nils-Göran
NG
Larsson
D000818:Animals; D001369:Axons / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004579:Electron Transport / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism*; D005804:Genes, Lethal; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse