scholarly journals The H+ Transporter SLC4A11: Roles in Metabolism, Oxidative Stress and Mitochondrial Uncoupling

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 197
Author(s):  
Joseph A. Bonanno ◽  
Raji Shyam ◽  
Moonjung Choi ◽  
Diego G. Ogando
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Oxidative Stress ◽  
Antioxidant Genes ◽  
Knock Out ◽  
Bicarbonate Transporter ◽  
Mitochondrial Superoxide ◽  
Transporter Family

Solute-linked cotransporter, SLC4A11, a member of the bicarbonate transporter family, is an electrogenic H+ transporter activated by NH3 and alkaline pH. Although SLC4A11 does not transport bicarbonate, it shares many properties with other members of the SLC4 family. SLC4A11 mutations can lead to corneal endothelial dystrophy and hearing deficits that are recapitulated in SLC4A11 knock-out mice. SLC4A11, at the inner mitochondrial membrane, facilitates glutamine catabolism and suppresses the production of mitochondrial superoxide by providing ammonia-sensitive H+ uncoupling that reduces glutamine-driven mitochondrial membrane potential hyperpolarization. Mitochondrial oxidative stress in SLC4A11 KO also triggers dysfunctional autophagy and lysosomes, as well as ER stress. SLC4A11 expression is induced by oxidative stress through the transcription factor NRF2, the master regulator of antioxidant genes. Outside of the corneal endothelium, SLC4A11’s function has been demonstrated in cochlear fibrocytes, salivary glands, and kidneys, but is largely unexplored overall. Increased SLC4A11 expression is a component of some “glutamine-addicted” cancers, and is possibly linked to cells and tissues that rely on glutamine catabolism.

scholarly journals Supplementation of T3Recovers Hypothyroid Rat Liver Cells from Oxidatively Damaged Inner Mitochondrial Membrane Leading to Apoptosis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Sutapa Mukherjee ◽  
Luna Samanta ◽  
Anita Roy ◽  
Shravani Bhanja ◽  
Gagan B. N. Chainy
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Membrane ◽  
Membrane Lipids ◽  
Antioxidant Defenses ◽  
Hepatocyte Apoptosis ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Oxidative Stress ◽  
Rat Liver Cells ◽  
Matrix Fraction ◽  
Complex I Activity

Hypothyroidism is a growing medical concern. There are conflicting reports regarding the mechanism of oxidative stress in hypothyroidism. Mitochondrial oxidative stress is pivotal to thyroid dysfunction. The present study aimed to delineate the effects of hepatic inner mitochondrial membrane dysfunction as a consequence of 6-n-propyl-2-thiouracil-induced hypothyroidism in rats. Increased oxidative stress predominance in the submitochondrial particles (SMP) and altered antioxidant defenses in the mitochondrial matrix fraction correlated with hepatocyte apoptosis. In order to check whether the effects caused by hypothyroidism are reversed by T3, the above parameters were evaluated in a subset of T3-treated hypothyroid rats. Complex I activity was inhibited in hypothyroid SMP, whereas T3supplementation upregulated electron transport chain complexes. Higher mitochondrial H2O2levels in hypothyroidism due to reduced matrix GPx activity culminated in severe oxidative damage to membrane lipids. SMP and matrix proteins were stabilised in hypothyroidism but exhibited increased carbonylation after T3administration. Glutathione content was higher in both. Hepatocyte apoptosis was evident in hypothyroid liver sections; T3administration, on the other hand, exerted antiapoptotic and proproliferative effects. Hence, thyroid hormone level critically regulates functional integrity of hepatic mitochondria; hypothyroidism injures mitochondrial membrane lipids leading to hepatocyte apoptosis, which is substantially recovered upon T3supplementation.

Abstract 410: Mitochondrial Uncoupling with CCCP Reverses Acute Hyperglycemia Induced Endothelial Dysfunction in Human Arterioles

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jingli Wang ◽  
David D Gutterman ◽  
Michael E Widlansky
Keyword(s):  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Mitochondrial Membrane ◽  
Oxidase Inhibitor ◽  
List Type ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Uncoupling ◽  
Acute Hyperglycemia ◽  
Mitochondrial Superoxide

Background : Acute hyperglycemia (HG) impairs endothelial function, which may be related to hyperpolarization of the inner mitochondrial membrane and excessive production of mitochondrial superoxide (ROS). Mitochondrial uncoupling agents could potentially reverse endothelial dysfunction due to HG in intact human arterioles. Methods : Human adipose arterioles were incubated in either euglycemic (NG, 5mM) or hyperglycemic (HG, 33mM) buffer for 4 hours. Vessels were then exposed to increasing doses of acetylcholine (ACh) in the presence and absence of NADPH oxidase inhibitor gp91ds-tat or CCCP, (100 nM), a mitochondrial membrane uncoupling agent. Vascular superoxide levels were also measured after incubation with NG and HG using a chemiluminescent probe (L-012) in the absence and presence of 1 and 2 above. Results : ACh-induced vasodilation was impaired by HG vs. NG control (P<0.001). This impairment was modestly reversed by gp91 ds-tat (P< 0.001), but endothelial function was completely restored to the level observed under euglycemic conditions by CCCP (P=0.008 vs. HG, P>0.90 vs. NG). Endothelium-dependent vasodilation in HG vessels was greater after CCCP compared to gp91ds-tat (P<0.001). L-NAME inhibited all dilation to ACh indicating endothelium-dependence (data not shown). HG induced an increase in superoxide relative to NG (P<0.001), which was similarly suppressed by gp91ds-tat (P = 0.001) and CCCP (P=0.002). Conclusion : HG-induced endothelial dysfunction is reversed with partial uncoupling of mitochondrial oxidative phosphorylation. Mitochondrial uncoupling more than NADPH oxidase blockade improves endothelial dysfunction due to HG.

scholarly journals Cytotoxicity and Mitochondrial Effects of Phenolic and Quinone-Based Mitochondria-Targeted and Untargeted Antioxidants on Human Neuronal and Hepatic Cell Lines: A Comparative Analysis

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1605
Author(s):  
Carlos Fernandes ◽  
Afonso J. C. Videira ◽  
Caroline D. Veloso ◽  
Sofia Benfeito ◽  
Pedro Soares ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Lines ◽  
Mitochondrial Membrane ◽  
Hepatic Cell ◽  
Therapeutic Application ◽  
Extracellular Acidification ◽  
Mitochondrial Oxidative Stress ◽  
Drug Candidates ◽  
Cellular Oxygen ◽  
Hepatic Cell Lines

Mitochondriotropic antioxidants (MC3, MC6.2, MC4 and MC7.2) based on dietary antioxidants and analogs (caffeic, hydrocaffeic, trihydroxyphenylpropanoic and trihydroxycinnamic acids) were developed. In this study, we evaluate and compare the cytotoxicity profile of novel mitochondria-targeted molecules (generally known as MitoCINs) on human HepG2 and differentiated SH-SY5Y cells with the quinone-based mitochondria-targeted antioxidants MitoQ and SkQ1 and with two non-targeted antioxidants, resveratrol and coenzyme Q10 (CoQ10). We further evaluate their effects on mitochondrial membrane potential, cellular oxygen consumption and extracellular acidification rates. Overall, MitoCINs derivatives reduced cell viability at concentrations about six times higher than those observed with MitoQ and SkQ1. A toxicity ranking for both cell lines was produced: MC4 < MC7.2 < MC3 < MC6.2. These results suggest that C-6 carbon linker and the presence of a pyrogallol group result in lower cytotoxicity. MC3 and MC6.2 affected the mitochondrial function more significantly relative to MitoQ, SkQ1, resveratrol and CoQ10, while MC4 and MC7.2 displayed around 100–1000× less cytotoxicity than SkQ1 and MitoQ. Based on the mitochondrial and cytotoxicity cellular data, MC4 and MC7.2 are proposed as leads that can be optimized to develop safe drug candidates with therapeutic application in mitochondrial oxidative stress-related diseases.

Abstract P150: Sex Difference of Hypertension in Spontaneously Hypertensive Rats: Role of Mitochondrial Oxidative Stress

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Rodrigo O Maranon ◽  
Carolina Dalmasso ◽  
Chetal N Patil ◽  
Jane F Reckelhoff
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Sex Difference ◽  
Spontaneously Hypertensive Rats ◽  
Pressor Response ◽  
Premenopausal Women ◽  
Hypertensive Rats ◽  
Mitochondrial Oxidative Stress ◽  
Spontaneously Hypertensive ◽  
Mitochondrial Superoxide

Men have higher blood pressure (BP) than premenopausal women. Pressor response to oxidative stress may be a major contributor to the sex difference in BP control. Mitochondrial oxidative stress is associated with hypertension; however, whether mitochondrial oxidative stress plays a role in the sex difference in BP is unknown. In the present study, we tested the hypothesis that mitochondrial oxidative stress contributes to the sex difference in BP regulation in spontaneously hypertensive rats (SHR). Young intact (iYMSHR) and castrated males (cYMSHR), and females SHR (YFSHR) (3 mos of age) were implanted with radiotelemeters, and after a 4 day baseline BP, were treated with mitoTempo (0.75 mg/kg/d, sc minipumps), a specific scavenger of mitochondrial superoxide, for 7 days. Following 10 days washout of mito-tempo, rats were treated with Tempol (30 mg/kg/day, po drinking water) for 7 days. iYMSHR have higher blood pressure (by telemetry) than cYMSHR and YFSHR (148±1 mmHg, n=5, vs 132±1 mmHg, n=5, and 139±1 mmHg, n=5; p<0.01, respectively). MitoTempo reduced BP by 6% in iYMSHR (147±1 vs 139±1, n=5; p<0.05) compared to females (3%: 139±1 vs 136±1; n=5; p: NS) and castrated males (4.5%: 132±1 vs 126±1, n=5; p<0.05). After 10 days washout, tempol reduced BP only in iYMSHR (144±1 vs 130±1 mmHg, n=5; p<0.05). Our results suggest that mitochondrial oxidative stress may contribute to BP regulation in male SHR, but has no effect in females. The data also suggest that the presence of testosterone is necessary for the pressor response to oxidative stress in males since Tempol had no effect on BP in castrated males. Further studies examining the effect of steroid hormones and mitochondria in BP regulation are necessary to elucidate the importance of mitochondrial oxidative stress on sex difference of hypertension.

Abstract 16: Progressive Alterations Of Mitochondrial Bioenergetics In The Kidney During The Development Of Salt-induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Namrata Tomar ◽  
Sunil M Kandel ◽  
Xiao Zhang ◽  
Nadezhda Zheleznova ◽  
Allen W Cowley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex Disease ◽  
Atp Synthesis ◽  
Control Group ◽  
Mitochondrial Uncoupling ◽  
Knock Out ◽  
Atp Production ◽  
Consumption Rates ◽  
Mitochondrial Efficiency ◽  
Salt Sensitive Hypertension

Hypertension is a complex disease and a leading cause of morbidity and mortality globally. Although oxidative stress and mitochondrial dysfunction have been found in the kidney in various models of hypertension, progressive alteration of mitochondrial oxidative phosphorylation (OxPhos) in the kidney during the development of salt-sensitive hypertension has not been characterized. The present study determined changes of OxPhos in kidneys of Dahl salt-sensitive (SS) rats before (0.4% NaCl diet; LS) and after switching to a high salt diet (4.0% NaCl; HS) during the development of hypertension. Mitochondria were isolated from the outer medulla (OM) and cortex of the kidney of SS rats fed a LS diet since weaning and studied at days 3, 7, 14 & 21 of a HS diet feeding. Oxygen consumption rates (OCR) were measured in mitochondria energized with pyruvate + malate as substrates for three different respiratory states using an Oroboros Oxygraph-2k Instrument. This includes i) leak state (in the absence of ADP), ii) ADP-stimulated state, and iii) uncoupled state (in the presence of an uncoupler FCCP). A biphasic pattern of ADP-stimulated OCR with progressive uncoupling was observed in both the renal OM and cortex. Mitochondrial efficiency for ATP synthesis was increased in the early phases of hypertension (3 & 7 days) but was severely compromised in the established phases of hypertension (14 & 21 days). This decreased mitochondrial efficiency was associated with uncoupling of OxPhos and high levels of oxidative stress which we hypothesized were due to mitochondrial ROS stimulation of membrane NOXs. To test this, experiments were performed in SS rats with double knock out (DKO) of the cytosolic subunit of NOX2 (p67 phox ) and NOX4 (SS p67phox-/-/Nox4-/- ). DKO SS rats were fed a HS diet and OCR of renal cortical and OM mitochondria was determined at days 7 and 14. In contrast to SS rats, the DKO SS rats fed a HS diet showed no significant differences in mitochondrial OCR in the cortex or OM, nor to a control group maintained on a LS diet. HS diet in SS rats initially increases the efficiency of renal cortical and medullary mitochondrial ATP production (days 1-7) followed by an enhanced ROS production with mitochondrial uncoupling and reduced efficiency of ATP production by the third week.

scholarly journals Metallothionein-I/II Knockout Mice Aggravate Mitochondrial Superoxide Production and Peroxiredoxin 3 Expression in Thyroid after Excessive Iodide Exposure

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Na Zhang ◽  
Lingyan Wang ◽  
Qi Duan ◽  
Laixiang Lin ◽  
Mohamed Ahmed ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Urinary Iodine ◽  
In Vitro Study ◽  
Superoxide Production ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Superoxide ◽  
Iodine Level ◽  
Significant Difference

Purpose. We aim to figure out the effect of metallothioneins on iodide excess induced oxidative stress in the thyroid.Methods. Eight-week-old MT-I/II knockout (MT-I/II KO) mice and background-matched wild-type (WT) mice were used. Mitochondrial superoxide production and peroxiredoxin (Prx) 3 expression were measured.Results. In in vitro study, more significant increases in mitochondrial superoxide production and Prx 3 expression were detected in the MT-I/II KO groups. In in vivo study, significantly higher concentrations of urinary iodine level were detected in MT-I/II KO mice in 100 HI group. Compared to the NI group, there was no significant difference existing in serum thyroid hormones level in either groups (P>0.05), while the mitochondrial superoxide production was significantly increased in 100 HI groups with significantly increased LDH activity and decreased relative cell viability. Compared to WT mice, more significant changes were detected in MT-I/II KO mice in 100 HI groups. No significant differences were detected between the NI group and 10 HI group in both the MT-I/II KO and WT mice groups (P>0.05).Conclusions. Iodide excess in a thyroid without MT I/II protection may result in strong mitochondrial oxidative stress, which further leads to the damage of thyrocytes.

scholarly journals Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress

Oncogene ◽  
2021 ◽  
Author(s):  
Xiaohe Hao ◽  
Wenqing Bu ◽  
Guosheng Lv ◽  
Limei Xu ◽  
Dong Hou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Oxidative Dna Damage ◽  
Underlying Mechanism ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Superoxide ◽  
Antineoplastic Effect ◽  
M Phase

AbstractReactive oxygen species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in cancer cells treated with anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. CHK1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in cancer therapy.

scholarly journals Old Yellow Enzymes, Highly Homologous FMN Oxidoreductases with Modulating Roles in Oxidative Stress and Programmed Cell Death in Yeast

2007 ◽  
Vol 282 (49) ◽  
pp. 36010-36023 ◽  
Author(s):  
Osama Odat ◽  
Samer Matta ◽  
Hadi Khalil ◽  
Sotirios C. Kampranis ◽  
Raymond Pfau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Antioxidant Activities ◽  
Ros Generation ◽  
Oxidized Glutathione ◽  
Wild Type ◽  
Antioxidant Genes ◽  
Knock Out ◽  
Chronological Aging

In a genetic screen to identify modifiers of Bax-dependent lethality in yeast, the C terminus of OYE2 was isolated based on its capacity to restore sensitivity to a Bax-resistant yeast mutant strain. Overexpression of full-length OYE2 suppresses Bax lethality in yeast, lowers endogenous reactive oxygen species (ROS), increases resistance to H2O2-induced programmed cell death (PCD), and significantly lowers ROS levels generated by organic prooxidants. Reciprocally, Δoye2 yeast strains are sensitive to prooxidant-induced PCD. Overexpression and knock-out analysis indicate these OYE2 antioxidant activities are opposed by OYE3, a highly homologous heterodimerizing protein, which functions as a prooxidant promoting H2O2-induced PCD in wild type yeast. To exert its effect OYE3 requires the presence of OYE2. Deletion of the 12 C-terminal amino acids and catalytic inactivation of OYE2 by a Y197F mutation enhance significantly survival upon H2O2-induced PCD in wild type cells, but accelerate PCD in Δoye3 cells, implicating the oye2p-oye3p heterodimer for promoting cell death upon oxidative stress. Unexpectedly, a strain with a double knock-out of these genes (Δoye2 oye3) is highly resistant to H2O2-induced PCD, exhibits increased respiratory capacity, and undergoes less cell death during the adaptive response in chronological aging. Simultaneous deletion of OYE2 and other antioxidant genes hyperinduces endogenous levels of ROS, promoting H2O2-induced cell death: in Δoye2 glr1 yeast high levels of oxidized glutathione elicited gross morphological aberrations involving the actin cytoskeleton and defects in organelle partitioning. Altering the ratio of reduced to oxidized glutathione by exogenous addition of GSH fully reversed these alterations. Based on this work, OYE proteins are firmly placed in the signaling network connecting ROS generation, PCD modulation, and cytoskeletal dynamics in yeast.

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