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Hypoxia causes autophagic stress and derangement of metabolic adaptation in a cell model of amyotrophic lateral sclerosis
Author(s) -
Cimini Sara,
Rizzardini Milena,
Biella Gloria,
Cantoni Lavinia
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12642
Subject(s) - amyotrophic lateral sclerosis , hypoxia (environmental) , derangement , autophagy , neuroscience , adaptation (eye) , medicine , biology , chemistry , oxygen , biochemistry , disease , organic chemistry , apoptosis , mathematics , combinatorics
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that affects motor neurons. The recruitment of autophagy (macroautophagy) and mitochondrial dysfunction are documented in amyotrophic lateral sclerosis patients and experimental models expressing mutant forms of Cu, Zn superoxide dismutase ( SOD 1) protein, but their impact in the disease remains unclear. Hypoxia is a stress closely related to the disease in patients and mutant SOD 1 mice; in individual cells, hypoxia activates autophagy and regulates mitochondrial metabolism as fundamental adaptive mechanisms. Our aim was to examine whether mutant SOD 1 changed this response. Hypoxia (1% O 2 for 22 h) caused greater loss of viability and more marked activation of caspase 3/7 in the motor neuronal NSC ‐34 cell line stably transfected with the G93A mutant human SOD 1 (G93A‐ NSC ) than in the one with the wild‐type SOD 1 ( WT ‐ NSC ) or in untransfected NSC ‐34. In the G93A‐ NSC cells, there was a more marked accumulation of the LC 3‐ II autophagy protein, attributable to autophagic stress; 3‐methyladenine, which acts on initiation of autophagy, fully rescued G93A‐ NSC viability and reduced the activation of caspase 3/7 indicating this was a secondary event; the metabolic handling of hypoxia was inappropriate possibly contributing to the autophagic stress. Our findings evidentiate that the G93A mutation of SOD 1 profoundly altered the adaptive metabolic response to hypoxia and this could increase the cell susceptibility to this stress.Hypoxia activates autophagy and modifies glycolysis and mitochondrial respiration as fundamental cell adaptive mechanisms. This stress is closely related to amyotrophic lateral sclerosis. The recruitment of autophagy and mitochondrial dysfunction are documented in patients and models expressing mutant Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. G93ASOD1 cells were more susceptible to hypoxia than wild‐type SOD1 cells and showed autophagic stress and inappropriate handling of energy metabolism. Defective adaptation to hypoxia may contribute to neurodegeneration.