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)