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.
PubMed.
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.
References:
Imai Y, Lu B.
Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder.
Curr Opin Neurobiol. 2011 Dec;21(6):935-41.
PubMed.
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X.
Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins.
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23.
PubMed.
Wang X, Su B, Fujioka H, Zhu X.
Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients.
Am J Pathol. 2008 Aug;173(2):470-82.
PubMed.
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X.
Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.
J Neurosci. 2009 Jul 15;29(28):9090-103.
PubMed.
Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E.
Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.
Nat Med. 2011 Mar;17(3):377-82. Epub 2011 Feb 20
PubMed.
Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH.
Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease.
Hum Mol Genet. 2012 Jan 15;21(2):406-20.
PubMed.
Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH.
Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage.
Hum Mol Genet. 2011 Apr 1;20(7):1438-55.
PubMed.
Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH.
Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.
Hum Mol Genet. 2011 Dec 1;20(23):4515-29.
PubMed.
Manczak M, Calkins MJ, Reddy PH.
Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage.
Hum Mol Genet. 2011 Jul 1;20(13):2495-509.
PubMed.
Magrané J, Hervias I, Henning MS, Damiano M, Kawamata H, Manfredi G.
Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities.
Hum Mol Genet. 2009 Dec 1;18(23):4552-64.
PubMed.
Comments
Case Western Reserve University
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.
References:
Imai Y, Lu B. Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder. Curr Opin Neurobiol. 2011 Dec;21(6):935-41. PubMed.
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23. PubMed.
Wang X, Su B, Fujioka H, Zhu X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. Am J Pathol. 2008 Aug;173(2):470-82. PubMed.
Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. PubMed.
Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med. 2011 Mar;17(3):377-82. Epub 2011 Feb 20 PubMed.
Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH. Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease. Hum Mol Genet. 2012 Jan 15;21(2):406-20. PubMed.
Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Hum Mol Genet. 2011 Apr 1;20(7):1438-55. PubMed.
Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet. 2011 Dec 1;20(23):4515-29. PubMed.
Manczak M, Calkins MJ, Reddy PH. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet. 2011 Jul 1;20(13):2495-509. PubMed.
Magrané J, Hervias I, Henning MS, Damiano M, Kawamata H, Manfredi G. Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Hum Mol Genet. 2009 Dec 1;18(23):4552-64. PubMed.
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