title: Downregulation of glutaredoxin but not glutathione loss leads to mitochondrial dysfunction in female mice CNS: implications in excitotoxicity.
abstract: Oxidative stress, excitotoxicity and mitochondrial dysfunction play synergistic roles in neurodegeneration. Maintenance of thiol homeostasis is important for normal mitochondrial function and dysregulation of protein thiol homeostasis by oxidative stress leads to mitochondrial dysfunction and neurodegeneration. We examined the critical roles played by the antioxidant, non-protein thiol, glutathione and related enzyme, glutaredoxin in maintaining mitochondrial function during excitotoxicity caused by beta-N-oxalyl amino-L-alanine (L-BOAA), the causative factor of neurolathyrism, a motor neuron disease involving the pyramidal system. L-BOAA causes loss of GSH and inhibition of mitochondrial complex I in lumbosacral cord of male mice through oxidation of thiol groups, while female mice are resistant. Reducing GSH levels in female mice CNS by pretreatment with diethyl maleate or L-propargyl glycine did not result in inhibition of complex I activity, unlike male mice. Further, treatment of female mice depleted of GSH with L-BOAA did not induce inhibition of complex I indicating that GSH levels were not critical for maintaining complex I activity in female mice unlike their male counterpart. Glutaredoxin, a thiol disulfide oxidoreductase helps maintain redox status of proteins and downregulation of glutaredoxin results in loss of mitochondrial complex I activity. Female mice express higher levels of glutaredoxin in certain CNS regions and downregulation of glutaredoxin using antisense oligonucleotides sensitizes them to L-BOAA toxicity seen as mitochondrial complex I loss. Ovariectomy downregulates glutaredoxin and renders female mice vulnerable to L-BOAA toxicity as evidenced by activation of AP1, loss of GSH and complex I activity indicating the important role of glutaredoxin in neuroprotection. Estrogen protects against mitochondrial dysfunction caused by excitotoxicity by maintaining cellular redox status through higher constitutive expression of glutaredoxin in the CNS. Therapeutic interventions designed to upregulate glutaredoxin may offer neuroprotection against excitotoxicity in motor neurons.
authors.affiliation: Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar 122050, India.
authors.forename: Latha
authors.initials: L
authors.lastname: Diwakar
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.forename: Jayasree
authors.initials: J
authors.lastname: Annepu
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ravindranath
mesh_terms: D000599:Amino Acids, Diamino / Q000633:toxicity; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D054477:Glutaredoxins; D005978:Glutathione / Q000378:metabolism; D007842:Lathyrism / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D016472:Motor Neuron Disease / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010088:Oxidoreductases / Q000378:metabolism*; D012727:Sex Characteristics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000599:Amino Acids, Diamino; D004967:Estrogens; D054477:Glutaredoxins; D018696:Neuroprotective Agents; D009498:Neurotoxins; C100126:oxalyldiaminopropionic acid; D010088:Oxidoreductases; D005978:Glutathione