Low melatonin as a contributor to SARS-CoV-2 disease

2020 ◽  
Vol 3 (4) ◽  
pp. 558-576
Author(s):  
Seithikurippu R Pandi-Perumal ◽  
Daniel P Cardinali ◽  
Russel J Reiter ◽  
Gregory M Brown
Keyword(s):  
Reactive Oxygen Species ◽  
Oxidative Phosphorylation ◽  
Pineal Gland ◽  
Oxygen Species ◽  
Cytokine Storm ◽  
Major Site ◽  
Immune Modulator ◽  
Inflammatory Agent ◽  
Site Of Action ◽  
Extrapineal Melatonin

That the pineal gland is a source of melatonin is widely known; however, by comparison, few know of the much larger pool of extrapineal melatonin. That pool is widely distributed in all animals, including those that do not have a pineal gland, e.g., insects.  Extrapineal melatonin is not released into the blood but is used locally to function as an antioxidant, anti-inflammatory agent, etc. A major site of action of peripherally-produced melatonin is the mitochondria where it neutralizes reactive oxygen species (ROS) that are generated during oxidative phosphorylation. Its role also includes major actions as an immune modulator reducing overreactions to foreign agents while simultaneously boosting immune processes. During a pandemic such as coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, melatonin is capable of suppressing the damage inflicted by the cytokine storm. The implications of melatonin in susceptibility and treatment of COVID-19 disease are discussed. 

scholarly journals AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture

2019 ◽  
Author(s):  
Dongqing Zheng ◽  
Jonathan H. Sussman ◽  
Matthew P. Jeon ◽  
Sydney T. Parrish ◽  
Alireza Delfarah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Oxygen Species

ABSTRACTOncogenes can generate metabolic vulnerabilities in cancer cells. Here, we tested how AKT and MYC affect the ability of cells to shift between respiration and glycolysis. Using immortalized mammary epithelial cells, we discovered that constitutively active AKT but not MYC induced cell death in galactose culture, where cells must rely on oxidative phosphorylation for energy generation. However, the negative effects of AKT were short-lived, and AKT-expressing cells recommenced growth after ~15 days in galactose. To identify the mechanisms regulating AKT-mediated cell death, we used metabolomics and found that AKT cells dying in galactose upregulated glutathione metabolism. Next, using proteomics, we discovered that AKT-expressing cells dying in galactose upregulated nonsense-mediated mRNA decay, a marker of sensitivity to oxidative stress. We therefore measured levels of reactive oxygen species (ROS) and discovered that galactose induced ROS in cells expressing AKT but not MYC. Additionally, ROS were required for the galactose-induced death of AKT-expressing cells. We then tested whether these findings could be replicated in breast cancer cell lines with constitutively active AKT signaling. Indeed, we found that galactose induced rapid cell death in breast cancer cell lines and that ROS were required for galactose-induced cell death. Together, our results demonstrate that AKT but not MYC induces a metabolic vulnerability in cancer cells, namely the restricted flexibility to use oxidative phosphorylation.ImplicationsThe discovery that AKT but not MYC restricts the ability to utilize oxidative phosphorylation highlights that therapeutics targeting tumor metabolism must be tailored to the individual genetic profile of tumors.

scholarly journals Trolox-Sensitive Reactive Oxygen Species Regulate Mitochondrial Morphology, Oxidative Phosphorylation and Cytosolic Calcium Handling in Healthy Cells

2012 ◽  
Vol 17 (12) ◽  
pp. 1657-1669 ◽  
Author(s):  
Felix Distelmaier ◽  
Federica Valsecchi ◽  
Marleen Forkink ◽  
Sjenet van Emst-de Vries ◽  
Herman G. Swarts ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Oxidative Phosphorylation ◽  
Reactive Oxygen ◽  
Cytosolic Calcium ◽  
Calcium Handling ◽  
Mitochondrial Morphology ◽  
Oxygen Species

Mitochondrial-derived reactive oxygen species influence ADP sensitivity, but not CPT-I substrate sensitivity

2018 ◽  
Vol 475 (18) ◽  
pp. 2997-3008 ◽  
Author(s):  
Pierre-Andre Barbeau ◽  
Paula M. Miotto ◽  
Graham P. Holloway
Keyword(s):  
Reactive Oxygen Species ◽  
Oxidative Phosphorylation ◽  
Acute Exercise ◽  
Adenine Nucleotide ◽  
Mitochondrial Protein ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Emission Rates ◽  
Mitochondrial Ros ◽  
Cpt I

The mechanisms regulating oxidative phosphorylation during exercise remain poorly defined; however, key mitochondrial proteins, including carnitine palmitoyltransferase-I (CPT-I) and adenine nucleotide translocase, have redox-sensitive sites. Interestingly, muscle contraction has recently been shown to increase mitochondrial membrane potential and reactive oxygen species (ROS) production; therefore, we aimed to determine if mitochondrial-derived ROS influences bioenergetic responses to exercise. Specifically, we examined the influence of acute exercise on mitochondrial bioenergetics in WT (wild type) and transgenic mice (MCAT, mitochondrial-targeted catalase transgenic) possessing attenuated mitochondrial ROS. We found that ablating mitochondrial ROS did not alter palmitoyl-CoA (P-CoA) respiratory kinetics or influence the exercise-mediated reductions in malonyl CoA sensitivity, suggesting that mitochondrial ROS does not regulate CPT-I. In contrast, while mitochondrial protein content, maximal coupled respiration, and ADP (adenosine diphosphate) sensitivity in resting muscle were unchanged in the absence of mitochondrial ROS, exercise increased the apparent ADP Km (decreased ADP sensitivity) ∼30% only in WT mice. Moreover, while the presence of P-CoA decreased ADP sensitivity, it did not influence the basic response to exercise, as the apparent ADP Km was increased only in the presence of mitochondrial ROS. This basic pattern was also mirrored in the ability of ADP to suppress mitochondrial H2O2 emission rates, as exercise decreased the suppression of H2O2 only in WT mice. Altogether, these data demonstrate that while exercise-induced mitochondrial-derived ROS does not influence CPT-I substrate sensitivity, it inhibits ADP sensitivity independent of P-CoA. These data implicate mitochondrial redox signaling as a regulator of oxidative phosphorylation.

Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production

2004 ◽  
Vol 286 (5) ◽  
pp. E852-E861 ◽  
Author(s):  
Lisa Bevilacqua ◽  
Jon J. Ramsey ◽  
Kevork Hagopian ◽  
Richard Weindruch ◽  
Mary-Ellen Harper
Keyword(s):  
Reactive Oxygen Species ◽  
Oxidative Phosphorylation ◽  
Metabolic Control ◽  
Calorie Restriction ◽  
Reactive Oxygen ◽  
Proton Leak ◽  
Ros Production ◽  
Oxygen Species ◽  
Medium Term ◽  
Time Points

Reductions in cellular oxygen consumption (V̇o2) and reactive oxygen species (ROS) production have been proposed as mechanisms underlying the anti-aging effects of calorie restriction (CR). Mitochondria are a cell's greatest “sink” for oxygen and also its primary source of ROS. The mitochondrial proton leak pathway is responsible for 20–30% of V̇o2 in resting cells. We hypothesized that CR leads to decreased proton leak with consequential decreases in V̇o2, ROS production, and cellular damage. Here, we report the effects of short-term (2-wk, 2-mo) and medium-term (6-mo) CR (40%) on rat muscle mitochondrial proton leak, ROS production, and whole animal V̇o2. Whole body V̇o2 decreased with CR at all time points, whereas mass-adjusted V̇o2 was normal until the 6-mo time point, when it was 40% lower in CR compared with control rats. At all time points, maximal leak-dependent V̇o2 was lower in CR rats compared with controls. Proton leak kinetics indicated that mechanisms of adaptation to CR were different between short- and medium-term treatments, with the former leading to decreases in protonmotive force (Δp) and state 4 V̇o2 and the latter to increases in Δp and decreases in state 4 V̇o2. Results from metabolic control analyses of oxidative phosphorylation are consistent with the idea that short- and medium-term responses are distinct. Mitochondrial H2O2 production was lower in all three CR groups compared with controls. Overall, this study details the rapid effects of short- and medium-term CR on proton leak, ROS production, and metabolic control of oxidative phosphorylation. Results indicate that a reduction in mitochondrial V̇o2 and ROS production may be a mechanism for the actions of CR.

scholarly journals Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3003
Author(s):  
Yun Haeng Lee ◽  
Ji Yun Park ◽  
Haneur Lee ◽  
Eun Seon Song ◽  
Myeong Uk Kuk ◽  
...  
Keyword(s):  
Energy Source ◽  
Reactive Oxygen Species ◽  
Oxidative Phosphorylation ◽  
Reactive Oxygen ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Oxygen Species ◽  
Metabolic Alterations ◽  
Age Related

Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.

scholarly journals Macrophages utilize mitochondrial fission to enhance mROS production during responses to Streptococcus pneumoniae

2019 ◽  
Author(s):  
Mohammed Mohasin ◽  
Katharin Balbirnie-Cumming ◽  
Emily Fisk ◽  
Elizabeth C. Prestwich ◽  
Clark D. Russell ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Streptococcus Pneumoniae ◽  
Oxidative Phosphorylation ◽  
Reactive Oxygen ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Fragmentation ◽  
Bacterial Killing ◽  
Form Complex

AbstractImmunometabolism and regulation of mitochondrial reactive oxygen species (mROS) control the immune effector phenotype of differentiated macrophages. Mitochondrial function requires dynamic fission and fusion, but whether effector function is coupled to altered dynamics during bacterial responses is unknown. We show that macrophage mitochondria undergo fission after 12 h of progressive ingestion of live Streptococcus pneumoniae (pneumococci), without evidence of Drp-1 phosphorylation at S616. Fission is associated with progressive reduction in oxidative phosphorylation but increased mROS generation. Fission is enhanced by mROS production, PI3Kγ signaling and by cathepsin B, but is independent of inflammasome activation or IL-1β generation. Inhibition of fission reduces bacterial killing. Fission is associated with Parkin recruitment to mitochondria, but not mitophagy. Fission occurs upstream of apoptosis induction and independently of caspase activation. During macrophage innate responses to bacteria mitochondria shift from oxidative phosphorylation and ATP generation to mROS production for microbicidal responses by undergoing fission.Author summaryChanges in metabolism regulate function in immune cells, including macrophages which are key cells in pathogen clearance. Mitochondria are cellular organelles that generate energy during metabolism but also mitochondrial reactive oxygen species (mROS) that contribute to bacterial killing. Mitochondria are dynamic organelles that form complex networks with varying degrees of fragmentation or fusion, but the functional consequences of these processes on macrophage function during bacterial infection are unknown. We show that sustained ingestion of live bacteria triggers mitochondrial fragmentation, reducing metabolism but enhancing mROS generation. Mitochondrial fragmentation is not part of a clearance pathway for damaged mitochondria and is initiated before signs of cell death. Macrophage signalling pathways activated during infection, and mROS generation, enhance mitochondrial fragmentation, and inhibition of pathways promoting fragmentation reduces bacterial killing. Overall, these findings suggest that responses to ingested bacteria trigger mitochondrial fragmentation, allowing mitochondria to switch from energy generation during metabolism to organelles facilitating bacterial killing.

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