Cardiac mitochondrial function, nitric oxide sensitivity and lipid composition following hypoxia acclimation in sablefish

High altitude environments challenge small mammals with persistent low ambient temperatures that require high rates of aerobic heat production in face of low O2 availability. An important component of thermogenic capacity in rodents is non-shivering thermogenesis (NST) mediated by uncoupled mitochondrial respiration in brown adipose tissue (BAT). NST is plastic, and capacity for heat production increases with cold acclimation. However, in lowland native rodents, hypoxia inhibits NST in BAT. We hypothesize that highland deer mice (Peromyscus maniculatus) overcome the hypoxic inhibition of NST through changes in BAT mitochondrial function. We tested this hypothesis using lab born and raised highland and lowland deer mice, and a lowland congeneric (P. leucopus), acclimated to either warm normoxia (25°C, 760 mmHg) or cold hypoxia (5°C, 430 mmHg). We determined the effects of acclimation and ancestry on whole-animal rates of NST, the mass of interscapular BAT (iBAT), and uncoupling protein (UCP)-1 protein expression. To identify changes in mitochondrial function, we conducted high-resolution respirometry on isolated iBAT mitochondria using substrates and inhibitors targeted to UCP-1. We found that rates of NST increased with cold hypoxia acclimation but only in highland deer mice. There was no effect of cold hypoxia acclimation on iBAT mass in any group, but highland deer mice showed increases in UCP-1 expression and UCP-1 stimulated mitochondrial respiration in response to these stressors. Our results suggest that highland deer mice have evolved to increase the capacity for NST in response to chronic cold hypoxia, driven in part by changes in iBAT mitochondrial function.

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NCX‐4016, a nitric oxide‐releasing aspirin, protects endothelial cells against apoptosis by modulating mitochondrial function

The FASEB Journal ◽

10.1096/fj.02-0297fje ◽

2002 ◽

Vol 16 (12) ◽

pp. 1645-1647 ◽

Cited By ~ 36

Author(s):

Stefano Fiorucci ◽

Andrea Mencarelli ◽

Roberta Mannucci ◽

Eleonora Distrutti ◽

Antonio Morelli ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Mitochondrial Function ◽

Nitric Oxide Releasing ◽

Ncx 4016

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Integrated analysis of the involvement of nitric oxide synthesis in mitochondrial proliferation, mitochondrial deficiency and apoptosis in skeletal muscle fibres

Scientific Reports ◽

10.1038/srep20780 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 1

Author(s):

Gabriela Silva Rodrigues ◽

Rosely Oliveira Godinho ◽

Beatriz Hitomi Kiyomoto ◽

Juliana Gamba ◽

Acary Souza Bulle Oliveira ◽

...

Keyword(s):

Nitric Oxide ◽

Mitochondrial Function ◽

Mitochondrial Diseases ◽

Integrated Analysis ◽

Muscle Fibres ◽

Mitochondrial Content ◽

Mitochondrial Dna Mutation ◽

Dna Mutation ◽

Mitochondrial Abnormalities ◽

Skeletal Muscle Fibres

Abstract Nitric oxide (NO) is an important signaling messenger involved in different mitochondrial processes but only few studies explored the participation of NO in mitochondrial abnormalities found in patients with genetic mitochondrial deficiencies. In this study we verified whether NO synthase (NOS) activity was altered in different types of mitochondrial abnormalities and whether changes in mitochondrial function and NOS activity could be associated with the induction of apoptosis. We performed a quantitative and integrated analysis of NOS activity in individual muscle fibres of patients with mitochondrial diseases, considering mitochondrial function (cytochrome-c-oxidase activity), mitochondrial content, mitochondrial DNA mutation and presence of apoptotic nuclei. Our results indicated that sarcolemmal NOS activity was increased in muscle fibres with mitochondrial proliferation, supporting the relevance of neuronal NOS in the mitochondrial biogenesis process. Sarcoplasmic NOS activity was reduced in cytochrome-c-oxidase deficient fibres, probably as a consequence of the involvement of NO in the regulation of the respiratory chain. Alterations in NOS activity or mitochondrial abnormalities were not predisposing factors to apoptotic nuclei. Taken together, our results show that NO can be considered a potential molecular target for strategies to increase mitochondrial content and indicate that this approach may not be associated with increased apoptotic events.

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Nitric oxide mediates lipopolysaccharide-induced alteration of mitochondrial function in cultured hepatocytes and isolated perfused liver

Hepatology ◽

10.1002/hep.1840180223 ◽

1993 ◽

Vol 18 (2) ◽

pp. 380-388 ◽

Cited By ~ 55

Author(s):

Iwao Kurose ◽

Shinzo Kato ◽

Hiromasa Ishii ◽

Dai Fukumura ◽

Soichiro Miura ◽

...

Keyword(s):

Nitric Oxide ◽

Mitochondrial Function ◽

Perfused Liver ◽

Cultured Hepatocytes ◽

Isolated Perfused Liver

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The possible role of nitric oxide and impaired mitochondrial function in ataxia due to severe vitamin E deficiency

Medical Hypotheses ◽

10.1016/s0306-9877(98)90010-x ◽

1998 ◽

Vol 50 (4) ◽

pp. 353-354 ◽

Cited By ~ 5

Author(s):

M.J. Fryer

Keyword(s):

Nitric Oxide ◽

Vitamin E ◽

Mitochondrial Function ◽

Vitamin E Deficiency ◽

Severe Vitamin

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Mitochondrial function and nitric oxide production in hippocampus and cerebral cortex of rats exposed to enriched environment

Brain Research ◽

10.1016/j.brainres.2010.01.017 ◽

2010 ◽

Vol 1319 ◽

pp. 44-53 ◽

Cited By ~ 14

Author(s):

S. Lores-Arnaiz ◽

M.R. Lores Arnaiz ◽

A. Czerniczyniec ◽

M. Cuello ◽

J. Bustamante

Keyword(s):

Nitric Oxide ◽

Cerebral Cortex ◽

Mitochondrial Function ◽

Enriched Environment ◽

Nitric Oxide Production ◽

Oxide Production

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Differential Mitochondrial Adaptation in Primary Vascular Smooth Muscle Cells from a Diabetic Rat Model

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/8524267 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Amy C. Keller ◽

Leslie A. Knaub ◽

P. Mason McClatchey ◽

Chelsea A. Connon ◽

Ron Bouchard ◽

...

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Mitochondrial Function ◽

High Glucose ◽

Vascular Function ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Muscle Cells ◽

Nutrient Stress

Diabetes affects more than 330 million people worldwide and causes elevated cardiovascular disease risk. Mitochondria are critical for vascular function, generate cellular reactive oxygen species (ROS), and are perturbed by diabetes, representing a novel target for therapeutics. We hypothesized that adaptive mitochondrial plasticity in response to nutrient stress would be impaired in diabetes cellular physiology via a nitric oxide synthase- (NOS-) mediated decrease in mitochondrial function. Primary smooth muscle cells (SMCs) from aorta of the nonobese, insulin resistant rat diabetes model Goto-Kakizaki (GK) and the Wistar control rat were exposed to high glucose (25 mM). At baseline, significantly greater nitric oxide evolution, ROS production, and respiratory control ratio (RCR) were observed in GK SMCs. Upon exposure to high glucose, expression of phosphorylated eNOS, uncoupled respiration, and expression of mitochondrial complexes I, II, III, and V were significantly decreased in GK SMCs (p<0.05). Mitochondrial superoxide increased with high glucose in Wistar SMCs (p<0.05) with no change in the GK beyond elevated baseline concentrations. Baseline comparisons show persistent metabolic perturbations in a diabetes phenotype. Overall, nutrient stress in GK SMCs caused a persistent decline in eNOS and mitochondrial function and disrupted mitochondrial plasticity, illustrating eNOS and mitochondria as potential therapeutic targets.

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Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase*

Critical Care Medicine ◽

10.1097/01.ccm.0000050074.82486.b2 ◽

2003 ◽

Vol 31 (2) ◽

pp. 353-358 ◽

Cited By ~ 91

Author(s):

Michael Boulos ◽

Mark E. Astiz ◽

Rajat S. Barua ◽

Mohammed Osman

Keyword(s):

Nitric Oxide ◽

Septic Shock ◽

Nitric Oxide Synthase ◽

Mitochondrial Function ◽

Oxide Synthase

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Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00540.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. R1494-R1501 ◽

Cited By ~ 22

Author(s):

Barbara Piotrkowski ◽

Cesar G. Fraga ◽

Elena M. V. de Cavanagh

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Mitochondrial Function ◽

Uncoupling Protein ◽

Rat Kidney ◽

Blood Pressure Reduction ◽

Renin Angiotensin System ◽

Renal Protection ◽

Kidney Mitochondria ◽

Ras Inhibition

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg·kg−1·day−1; Enal), or a NO synthase (NOS) inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME) (1 mg·kg−1·day−1), or both (Enal+l-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by l-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. l-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by l-NAME cotreatment. In Enal, kidney mitochondria H2O2 production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by l-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.

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