Magrané J, Sahawneh MA, Przedborski S, Estévez ÁG, Manfredi G.
Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons.
J Neurosci. 2012 Jan 4;32(1):229-42.
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This is a very well-executed study with very careful and detailed measurement of mitochondrial morphology and transport in motor neurons in an ALS model, and which extends the authors’ previous findings (Magrané et al., 2009). Mitochondrial Dendra is a very useful tool, but this is not the novelty here, since the same mitoDendra is already widely used by many groups. In this study, the authors convincingly demonstrated that mutant SOD1 impaired mitochondrial fusion and retrograde transport of mitochondria only in motor neurons. Of more pathogenic significance is that they found mitochondrial fragmentation progresses from distal to proximal segments over time (at five days in vitro, only distal segments demonstrated fragmented mitochondria, while at DIV10, both distal and proximal mitochondria fragment). That anterograde-moving mitochondria in mutant SOD1 motor neurons have lower mitochondrial membrane potential than those in controls supports a critical role of mitochondria dysfunction in the dying back mechanism of the SOD1-FALS model. They also confirmed the correlation between lack of mitochondrial support and synaptic abnormalities (Wang et al., 2009).
Overall, this study convincingly demonstrated that mutant SOD1 affects mitochondrial dynamics, adding ALS to the expanding list of neurodegenerative diseases involving abnormal mitochondrial dynamics, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease (Wang et al., 2008; Wang et al., 2008; Wang et al., 2009; Shirendeb et al., 2012; 2011; Manczak et al., 2011; Calkins et al., 2011; Song et al., 2011; Imai and Lu, 2011). These studies suggest that abnormal mitochondrial dynamics may be a common downstream pathway mediating or amplifying mitochondrial and neuronal dysfunction during the course of neurodegeneration. It is, therefore, of interest to determine how mutant SOD1 affects mitochondrial dynamics. (Is fission affected? Is it necessary for mutant SOD1 to interact with mitochondria? How does mutant SOD1 interact with the fission/fusion machinery?) It will also be interesting to know if SOD1 shares similar mechanisms with other pathogenic proteins.
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Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease.
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Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH.
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Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities.
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