Neuroprotection through Stimulation of Mitochondrial Antioxidant Protein Expression

Abstract

Abstract. Oxidative stress and loss of cellular Ca2+ homeostasis are closely linked and are common denominators in the pathophysiology of many neurodegenerative diseases and acute disorders of the nervous system. Mitochondria are major targets of oxidative stress and abnormal intracellular Ca 2+ , as both can cause bioenergetic failure through synergistic activation of the mitochondrial inner membrane permeability transition pore. Opening of this molecularly ill-defined pore causes both collapse of the membrane potential, which drives oxidative phosphorylation, and release of small metabolites, including pyridine nucleotides and glutathione, which are necessary for energy metabolism and defense against oxidative stress. Expression of genes coding for many antioxidant defense proteins is regulated by the Nrf2 transcriptional activating factor. Translocation of this protein from the cytosol to the nucleus is stimulated by oxidative stress and by specific agents that either react with cysteine sulfhydryl groups present on the protein KEAP1, that normally binds and restricts Nrf2 translocation, or that stimulate serine phosphorylation of Nrf2. Recent evidence indicates that mitochondria are a target of the cytoprotective gene expression induced by Nrf2 and that this pathway can increase resistance to redox-regulated opening of the permeability transition pore. Pharmacologic stimulation of the Nrf2 system and its protection against mitochondrial bioenergetic dysfunction may therefore constitute a powerful mechanism for both pre-conditioning against neurodegeneration and for post-conditioning against neural cell death associated with acute neurologic injury.Keywords: Antioxidant, bioenergetics, calcium, cerebral ischemia, neurodegeneration, Nrf2, oxidative stress, permeability transition pore are located at mitochondria or that are extramitochondrial but have strong secondary effects on mitochondrial bioenergetic or apoptotic activities. The most acute influence of ROS/RNS on mitochondria is mediated by oxidative modifications of proteins present in the electron transport chain (ETC) [1,2], other metabolic proteins, e.g., pyruvate dehydrogenase aconitase and α-ketogluatarate dehydrogenase [3][4][5], and the inner membrane permeability transition pore (PTP) [6,7]. Oxidation of cardiolipin, a phospholipid primarily lo- OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN NEURODEGENERATION

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

“…mPTP opening leads to a collapse of membrane potential and release of small metabolites, including pyridine nucleotides and glutathione, which are necessary for energy metabolism and defences against oxidative stress. Recent evidence indicates that New drug targets in depression 137 mitochondria are a target of the cytoprotective gene expression induced by Nrf2 and that this pathway protects against redox-regulated opening of the mPTP (Greco and Fiskum 2010).…”

Novel Mitochondrial Targets for Neuroprotection

“…acid cycle enzymes, the mitochondria-specific phospholipid, cardiolipin, and DNA (Andreyev et al, 2005;Sparvero et al, 2010;Chaturvedi and Beal, 2008). Oxidative stress also greatly increases the sensitivity of PTP opening by Ca 2 + (Greco and Fiskum, 2010b). Due to the high rate of mitochondrial ROS production and the critical impact that oxidative damage to mitochondrial metabolism has on cell survival, mitochondria possess numerous systems for ROS detoxification and for inhibiting or reversing oxidative molecular modifications (Andreyev et al, 2005).…”

Identification and Functional Studies of a New Nrf2 Partner IQGAP1: A Critical Role in the Stability and Transactivation of Nrf2

“…As just discussed, many proteins have been implicated in Nrf2 signaling; however, the precise and the exact molecular mechanisms of Nrf2 signaling remain to be further elucidated, particularly under different cellular perturbations such as intracellular calcium flux, as we have shown previously that calcium would impact Nrf2 signaling (9,16,42). Hence, in this study, we embarked on a search for additional proteins as potential Nrf2 interacting partners in order to have a better and more comprehensive understanding of the molecular signaling mechanisms of Nrf2 and Nrf2's regulation of downstream target genes such as antioxidant enzyme HO-1.…”