The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress and influence of mutation-type

• Published in: PloS one 2013-06, Vol.8 (6), p.e68256
• Main Authors: Richardson, Katie, Allen, Scott P, Mortiboys, Heather, Grierson, Andrew J, Wharton, Stephen B, Ince, Paul G, Shaw, Pamela J, Heath, Paul R
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyotrophic lateral sclerosis; Animals; Bioenergetics; Biology; Cell death; Cell Death - genetics; Cell Line; Cell Respiration - drug effects; Cell Respiration - genetics; Cell Survival - drug effects; Cell Survival - genetics; Cellular manufacture; Defects; Degeneration; Electron transport; Energy Metabolism - drug effects; Energy Metabolism - genetics; Glycolysis; Glycolysis - drug effects; Glycolysis - genetics; Humans; Hydrogen; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Kinases; Medicine; Membrane potential; Metabolism; Mice; Mitochondria; Motor neurons; Motor Neurons - drug effects; Motor Neurons - metabolism; Mutation; Neuroblastoma; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Oxygen; Oxygen consumption; Oxygen Consumption - drug effects; Oxygen Consumption - genetics; Pathogenesis; Reactive Oxygen Species - metabolism; Respiration; Rodents; Studies; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Transgenes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068256

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation of the SOD1 protein increases metabolic functional susceptibility to oxidative stress. Here we used a motor neuron-like cell line (NSC34) stably transfected with various human mutant SOD1 transgenes (G93A, G37R, H48Q) to investigate the impact of oxidative stress on cell viability and metabolic function within intact cells. NSC34 cells expressing mutant SOD1 showed a dose dependent reduction in cell viability when exposed to oxidative stress induced by hydrogen peroxide, with variation between mutations. The G93A transfectants showed greater cell death and LDH release compared to cells transfected with the other SOD1 mutations, and H48Q showed an accelerated decline at later time points. Differences in mitochondrial bioenergetics, including mitochondrial respiration, coupling efficiency and proton leak, were identified between the mutations, consistent with the differences observed in viability. NSC34 cells expressing G93A SOD1 displayed reduced coupled respiration and mitochondrial membrane potential compared to controls. Furthermore, the G93A mutation had significantly increased metabolic susceptibility to oxidative stress, with hydrogen peroxide increasing ROS production, reducing both cellular oxygen consumption and glycolytic flux in the cell. This study highlights bioenergetic defects within a cellular model of ALS and suggests that oxidative stress is not only detrimental to oxygen consumption but also glycolytic flux, which could lead to an energy deficit in the cell.