Mitochondrial Dynamics and Bioenergetic Dysfunction Is Associated with Synaptic Alterations in Mutant SOD1 Motor Neurons
Open Access
- 4 January 2012
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 32 (1), 229-242
- https://doi.org/10.1523/jneurosci.1233-11.2012
Abstract
Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild-type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons,in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild-type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS.Keywords
This publication has 49 references indexed in Scilit:
- ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein importProceedings of the National Academy of Sciences of the United States of America, 2010
- Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALSNature Neuroscience, 2010
- Mitochondrial dysfunction and intracellular calcium dysregulation in ALSMechanisms of Ageing and Development, 2010
- Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALSNeuron, 2010
- Motor Coordination via a Tug-of-War Mechanism Drives Bidirectional Vesicle TransportCurrent Biology, 2010
- Ca2+-dependent regulation of mitochondrial dynamics by the Miro–Milton complexThe International Journal of Biochemistry & Cell Biology, 2009
- The Ψ m depolarization that accompanies mitochondrial Ca 2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminalsProceedings of the National Academy of Sciences of the United States of America, 2009
- Fission and selective fusion govern mitochondrial segregation and elimination by autophagyThe EMBO Journal, 2008
- Engineering of a monomeric green-to-red photoactivatable fluorescent protein induced by blue lightNature Biotechnology, 2006
- The GTPase dMiro Is Required for Axonal Transport of Mitochondria to Drosophila SynapsesNeuron, 2005