The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

• Published in: Molecular biology reports 2020-07, Vol.47 (7), p.5587-5620
• Main Authors: Morris, G., Walder, K. R., Berk, M., Marx, W., Walker, A. J., Maes, M., Puri, B. K.
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Animal Anatomy; Animal Biochemistry; Antioxidants; Bioenergetics; Biomedical and Life Sciences; Bipolar disorder; Coenzyme Q10; Complications; Detoxification; Electron transport; Forkhead protein; Glutathione; Histology; Hydrogen peroxide; Life Sciences; Mental disorders; Mitochondria; Morphology; NAD; NADPH; Oral administration; Oxidative stress; Pathology; Peroxiredoxin; Reactive nitrogen species; Reactive oxygen species; Review; Schizophrenia; SIRT1 protein; Therapeutic applications; Thioredoxin; Transcription factors; Ubiquinone
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-020-05590-5

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H 2 O 2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD + depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD + -induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD + precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD + in the brain and periphery following oral administration; coenzyme Q 10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N -acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.