Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons

Human Molecular Genetics, Nov 2012

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.

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Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons

Human Molecular Genetics Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons Seungmin Lee 2 Fredrik H. Sterky 2 Arnaud Mourier 0 Mu¨ gen Terzioglu 0 Staffan Cullheim 1 Lars Olson 1 Nils-Go¨ ran Larsson 0 2 0 Max Planck Institute for Biology of Ageing , Gleueler Str. 50a, 50931 Cologne , Germany 1 Department of Neuroscience, Karolinska Institutet , Retzius va ̈ g 8, SE-171 77 Stockholm , Sweden 2 Department of Laboratory Medicine 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. - INTRODUCTION Parkinson’s disease (PD) is a common neurodegenerative condition characterized by loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNc). Although other populations of neurons are also affected, the hallmark motor symptoms of PD are caused by the resulting DA deficiency in the striatum, the area to which these DA neurons project. The pathophysiological events that lead to the degeneration of DA neurons are unclear, but may involve mitochondrial dysfunction (1). A distinct form of PD, autosomal recessive juvenile parkinsonism (AR-JP), is caused by mutations in the genes PTEN-induced kinase 1 (PINK1), Parkin and DJ-1. Several genes mutated in AR-JP have been linked to the regulation of mitochondrial function. The E3 ubiquitin ligase Parkin and the mitochondrial kinase PINK1 act in a common pathway suggested to be involved in mitochondrial quality control. In cell lines, depolarization of the membrane potential across the inner mitochondrial membrane induces a PINK1-dependent recruitment of cytosolic Parkin to the mitochondrial outer membrane (2). The precise role of Parkin on the outer mitochondrial surface remains to be established and the link to the degeneration of DA neurons is not well understood (3). We have previously addressed the consequences of mitochondrial dysfunction in DA neurons by creating MitoPark mice that have DA-specific disruption of mitochondrial transcription factor A (4), a dual function protein required for mitochondrial transcription initiation and for packaging of mtDNA into nucleoids (5,6). These mice develop severe motor symptoms due to progressive loss of DA neurons in SNc. The degenerating DA neurons in MitoPark mice have abnormal mitochondrial ultrastructure and a fragmented mitochondrial network. Furthermore, the DA neurons in MitoPark mice develop large, dense and membranous intracellular bodies derived from abnormal mitochondria, and the supply of mitochondria to their distal axons is impaired (4,7). Mitochondria form a functionally interconnected network in the cell by continuous fission and fusion (8,9). Mitochondrial dynamics is essential for embryonic development and studies in differentiated tissues have shown that continuous fission and fusion of mitochondria is necessary for maintaining mtDNA and oxidative phosphorylation capacity (10 – 12). Mutations in genes regulating mitochondrial fusion and fission cause human neurodegenerative diseases. For instance, mutations in OPA1 cause atrophy of the optic nerve (13) and mutations in MFN2 cause a form of hereditary motor and sensory neuropathy (14). It is believed that mitochondrial fusion contributes to maintaining function by allowing an exchange of mtDNA and other matrix components (8). Fission events fragment the mitochondrial network into smaller units to allow mitochondrial transport to different subcellular localizations, such as nerve terminals. Fission has (...truncated)


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Seungmin Lee, Fredrik H. Sterky, Arnaud Mourier, Mügen Terzioglu, Staffan Cullheim, Lars Olson, Nils-Göran Larsson. Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons, Human Molecular Genetics, 2012, pp. 4827-4835, 21/22, DOI: 10.1093/hmg/dds352