Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication

Li, Faith C.H.; Yen, Jiin Cherng; Chan, Samuel H.H.; Chang, Alice Y.W.

doi:10.1371/journal.pone.0030589

Cited by 21 publications

(21 citation statements)

References 63 publications

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“…Complex II couples the oxidation of succinate to fumarate in the matrix with the reduction of ubiquinone in the membrane [19]. To assess complex II activity directly we measured the production of ubiquinol [15], which demonstrated that HFHS feeding caused a marked decrease in complex II activity. Complex II consists of four nuclear-encoded proteins - SDH subunits A, B, C and D. SDHA and SDHB are exposed to the matrix, while SDHC and SDHD are in the inner membrane [20].…”

Section: Discussionmentioning

confidence: 99%

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High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

Sverdlov¹,

Elezaby²,

Behring³

et al. 2015

Journal of Molecular and Cellular Cardiology

106

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Background Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM. Methods and results Male C57Bl/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8 months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB. Conclusions MHD due to consumption of a HFHS “Western” diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II.

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Section: Discussionmentioning

confidence: 99%

“…Complex II enzyme activity of isolated mitochondria was measured using microplate assay kit (Abcam/Mitosciences ab109908/MS241), as previously described [15]. In this assay kit, complex II is immunocaptured within the wells of the microplate.…”

Section: Methodsmentioning

confidence: 99%

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

Sverdlov¹,

Elezaby²,

Behring³

et al. 2015

Journal of Molecular and Cellular Cardiology

106

View full text Add to dashboard Cite

show abstract

“…Complex II enzyme activity of isolated mitochondria was measured using microplate assay kit (Abcam/Mitosciences ab109908/MS241), as previously described [20]. In this assay kit, complex II was immunocaptured within the wells of the microplate.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload

Elezaby

Sverdlov

et al. 2015

Journal of Molecular and Cellular Cardiology

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Background Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-specific overexpression of the fatty acid transport protein FATP1 have increased cardiomyocyte FA uptake and develop MHD in the absence of systemic lipotoxicity, obesity or diabetes. We utilized this model to assess 1) the effect of cardiomyocyte lipid accumulation on mitochondrial structure and energetic function and 2) the role of lipid-driven transcriptional regulation, signaling, toxic metabolite accumulation, and mitochondrial oxidative stress in lipid-induced MHD. Methods Cardiac lipid species, lipid-dependent signaling, and mitochondrial structure / function were examined from FATP1 mice. Cardiac structure and function were assessed in mice overexpressing both FATP1 and mitochondrial-targeted catalase. Results FATP1 hearts exhibited a net increase (+12%) in diacylglycerol, with increases in several very long-chain diacylglycerol species (+160-212%, p<0.001) and no change in ceramide, sphingomyelin, or acylcarnitine content. This was associated with an increase in phosphorylation of PKCα and PKCδ, and a decrease in phosphorylation of AKT and expression of CREB, PGC1α, PPARα and the mitochondrial fusion genes MFN1, MFN2 and OPA1. FATP1 overexpression also led to marked decreases in mitochondrial size (-49%, p<0.01), complex II-driven respiration (-28.6%, p<0.05), activity of isolated complex II (-62%, p=0.05), and expression of complex II subunit B (SDHB) (-60% and -31%, p<0.01) in the absence of change in ATP synthesis. Hydrogen peroxide production was not increased in FATP1 mitochondria, and cardiac hypertrophy and diastolic dysfunction were not attenuated by overexpression of catalase in mitochondria in FATP1 mice. Conclusions Excessive delivery of FAs to the cardiac myocyte in the absence of systemic disorders leads to activation of lipid-driven signaling and remodeling of mitochondrial structure and function.

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“…Nonetheless, under pathological conditions, our laboratory has demonstrated in comatose patients that irreversible loss of baroreflex-mediated sympathetic vasomotor tone is a hallmark for brain death12131415. We further identified that nitrosative stress in key nuclei of the neural circuit is the culprit for the defunct baroreflex16 in animal models of brain death16171819202122232425. Intriguingly, patients with alcoholic cirrhosis exhibit reduced baroreflex sensitivity26, and the degree of decreased HR variability is related to the severity of HE in patients with cirrhosis27.…”

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confidence: 91%

Nitrosative Stress-Induced Disruption of Baroreflex Neural Circuits in a Rat Model of Hepatic Encephalopathy: A DTI Study

Tsai

Chan

et al. 2017

Sci Rep

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The onset of hepatic encephalopathy (HE) in liver failure is associated with high mortality; the underlying mechanism is undecided. Here we report that in an acute liver failure model employing intraperitoneal administration of thioacetamide in Sprague-Dawley rats, diffusion weighted imaging revealed a progressive reduction in apparent diffusion coefficient in the brain stem. Diffusion tensor imaging further showed that the connectivity between nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents in brain stem and rostral ventrolateral medulla (RVLM), the origin of sympathetic innervation of blood vessels, was progressively disrupted until its disappearance, coincidental with the irreversible cessation of baroreflex-mediated sympathetic vasomotor tone signifying clinically the occurrence of brain death. In addition, superoxide, nitric oxide, peroxynitrite and ammonia levels in the NTS or RVLM were elevated, alongside swelling of astroctytes. A scavenger of peroxynitrite, but not an antioxidant, delivered intracisternally reversed all these events. We conclude that nitrosative stress because of augmented peroxynitrite related to accumulation of ammonia and swelling of astrocytes in the NTS or RVLM, leading to cytotoxic edema in the brain stem and severance of the NTS-RVLM connectivity, underpins the defunct baroreflex-mediated sympathetic vasomotor tone that accounts for the high mortality associated with HE.

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Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication

Cited by 21 publications

References 63 publications

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload

Nitrosative Stress-Induced Disruption of Baroreflex Neural Circuits in a Rat Model of Hepatic Encephalopathy: A DTI Study

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