Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases

Abstract

Stroke is one of the leading causes of morbidity and mortality worldwide. A main cause of brain damage by stroke is ischemia-reperfusion (IR) injury due to the increased production of reactive oxygen species (ROS) and energy failure caused by changes in mitochondrial metabolism. Ischemia causes a build-up of succinate in tissues and changes in the mitochondrial NADH: ubiquinone oxidoreductase (complex I) activity that promote reverse electron transfer (RET), in which a portion of the electrons derived from succinate are redirected from ubiquinol along complex I to reach the NADH dehydrogenase module of complex I, where matrix NAD+ is converted to NADH and excessive ROS is produced. RET has been shown to play a role in macrophage activation in response to bacterial infection, electron transport chain reorganization in response to changes in the energy supply, and carotid body adaptation to changes in the oxygen levels. In addition to stroke, deregulated RET and RET-generated ROS (RET-ROS) have been implicated in tissue damage during organ transplantation, whereas an RET-induced NAD+/NADH ratio decrease has been implicated in aging, age-related neurodegeneration, and cancer. In this review, we provide a historical account of the roles of ROS and oxidative damage in the pathogenesis of ischemic stroke, summarize the latest developments in our understanding of RET biology and RET-associated pathological conditions, and discuss new ways to target ischemic stroke, cancer, aging, and age-related neurodegenerative diseases by modulating RET.

Hydrogen Sulfide: An Emerging Regulator of Oxidative Stress and Cellular Homeostasis—A Comprehensive One-Year Review

“…It attenuates mitochondrial ROS production, promotes mitochondrial biogenesis, and blocks the opening of mitochondrial permeability transition pores (mPTP). Under oxidative insults, these actions significantly preserve mitochondrial integrity, function, and cell survival [ 78 , 79 ].…”

Association of sensitivity to thyroid hormones with all-cause mortality in euthyroid US adults: a nationwide cohort study

“…In contrast, these individuals exhibit symptoms of thyrotoxicosis in other tissues that typically express TRα1 predominantly, such as the heart, bone, muscle, and adipose tissue, leading to various metabolic disorders ( 25 , 42 ). In addition, excessive TH levels can produce reactive oxygen species ( 43 ), which might trigger and maintain cell damage, induce physiological abnormalities, and facilitate disease progression ( 44 , 45 ). Furthermore, participants with a risk of mortality might be in a frailty status, such as starvation, chronic inflammation, impaired liver function, and sarcopenia, which may play a role in the impairment of peripheral T4 deiodination ( 38 ).…”

Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress

“…The ETC, responsible for ATP production, becomes a significant source of ROS as electrons leak prematurely and interact with molecular oxygen. This leakage occurs primarily at complexes I and III along the respiratory chain, leading to the overproduction of superoxide anions [ 19 ].…”

“…Xanthine oxidase catalyses the conversion of hypoxanthine and xanthine to uric acid, producing ROS as by-products [17,18] Electron leakage occurs at various points along the respiratory chain on the mitochondria, particularly at complex I and complex III, and is responsible for ROS generation [19] Differential expression of neuronal nitric oxide synthase (nNOS) induces nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) with the subsequent nitric oxide production [12] Nitric oxide reacts with superoxide to produce peroxynitrite [5] Peroxynitrite induces direct nitrosative damage/tyrosine nitration of Keap1 (preventing Nrf2 from being activated with its antioxidant activity) and TP53-induced glycolysis and apoptosis regulator (TIGAR) with a subsequent impaired generation of NADPH [12] While hypoxia-inducible factor-1 (HIF-1) activation during ischemia is generally regarded as protective by enhancing VEFG generation and stimulating angiogenesis, its role becomes more nuanced during reperfusion by promoting blood-brain barrier disruption mainly through pericytes [20] Nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor upregulates multiple antioxidant response elements (AREs), conferring cytoprotective factors to the cell [21] Lipid Peroxidation Fe 2+ produces ROS and promotes lipid peroxidation [22] Malondialdehyde (reactive aldehydes) can form adducts with cellular proteins and nucleic acids, contributing to cellular dysfunction [23] 4-Hydroxynonenal is primarily produced during the peroxidation of omega 6 polyunsaturated fatty acids [23] Low-density lipoprotein (LDL) molecules could become highly oxidised to trigger macrophages activation and apoptosis [23] ROS could participate in forming F2-isoprostanes through arachidonic acid oxidation [24] Acyl-CoA synthetase long-chain family member 4 (ACSL4) facilitates the incorporation of polyunsaturated fatty acids into phospholipids, contributing to lipid peroxidation [25] Nuclear receptor coactivator 4 (NCOA4) facilitates the selective autophagic degradation of ferritin, releasing iron and promoting the Fenton reaction, contributing to lipid peroxidation [26] Excitotoxicity Glutamate activates the NMDAR, inducing a large increase in intracellular Ca 2+ concentration, directly stimulating ROS/RNS production [5,27] Inflammation Microglia display a pro-inflammatory (M1) subtype, producing multiple pro-inflammatory cytokines such as the TNFα, interferon-gamma (IFN-γ) IL-1β, IL-6, and IL-12 [28,29] Microglia display an anti-inflammatory (M2) subtype, expressing anti-inflammatory cytokines, including IL-10, transforming growth factor beta (TGF-β), insulin-like growth factor 1 (IG...…”