scholarly journals Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshifumi Ohashi ◽  
Nobunori Takahashi ◽  
Kenya Terabe ◽  
Saho Tsuchiya ◽  
Toshihisa Kojima ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mitochondrial Respiration ◽  
Culture Media ◽  
Metabolic Reprogramming ◽  
Cartilage Explants ◽  
Mitochondrial Activity ◽  
Metabolic Dysfunction ◽  
Osteoarthritic Cartilage ◽  
Novel Approach ◽  
Functional Features

AbstractMetabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.

scholarly journals Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis

2020 ◽  
Author(s):  
Yoshifumi Ohashi ◽  
Nobunori Takahashi ◽  
Kenya Terabe ◽  
Saho Tsuchiya ◽  
Toshihisa Kojima ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mitochondrial Respiration ◽  
Culture Media ◽  
Metabolic Reprogramming ◽  
Cartilage Explants ◽  
Mitochondrial Activity ◽  
Metabolic Dysfunction ◽  
Osteoarthritic Cartilage ◽  
Atp Production ◽  
Functional Features

Abstract Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration for ATP production. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.

scholarly journals Identification of Potential Calorie Restriction-Mimicking Yeast Mutants with Increased Mitochondrial Respiratory Chain and Nitric Oxide Levels

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Bin Li ◽  
Craig Skinner ◽  
Pablo R. Castello ◽  
Michiko Kato ◽  
Erin Easlon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Calorie Restriction ◽  
Mitochondrial Respiration ◽  
Molecular Mechanisms ◽  
Mitochondrial Respiratory Chain ◽  
Yeast Cells ◽  
Mitochondrial Activity ◽  
No Production ◽  
Hypoxic Conditions ◽  
Yeast Mutants

Calorie restriction (CR) induces a metabolic shift towards mitochondrial respiration; however, molecular mechanisms underlying CR remain unclear. Recent studies suggest that CR-induced mitochondrial activity is associated with nitric oxide (NO) production. To understand the role of mitochondria in CR, we identify and studySaccharomyces cerevisiaemutants with increased NO levels as potential CR mimics. Analysis of the top 17 mutants demonstrates a correlation between increased NO, mitochondrial respiration, and longevity. Interestingly, treating yeast with NO donors such as GSNO (S-nitrosoglutathione) is sufficient to partially mimic CR to extend lifespan. CR-increased NO is largely dependent on mitochondrial electron transport and cytochrome c oxidase (COX). Although COX normally produces NO under hypoxic conditions, CR-treated yeast cells are able to produce NO under normoxic conditions. Our results suggest that CR may derepress some hypoxic genes for mitochondrial proteins that function to promote the production of NO and the extension of lifespan.

scholarly journals Glial Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

2021 ◽  
pp. 1-9
Author(s):  
Patricia Cassina ◽  
Ernesto Miquel ◽  
Laura Martínez-Palma ◽  
Adriana Cassina
Keyword(s):  
Motor Neuron ◽  
Disease Progression ◽  
Glial Cells ◽  
Mitochondrial Function ◽  
Neurodegenerative Disorder ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Neuron Death ◽  
Energy Demands ◽  
Aberrant Glial Cells

ALS is a human neurodegenerative disorder that induces a progressive paralysis of voluntary muscles due to motor neuron loss. The causes are unknown, and there is no curative treatment available. Mitochondrial dysfunction is a hallmark of ALS pathology; however, it is currently unknown whether it is a cause or a consequence of disease progression. Recent evidence indicates that glial mitochondrial function changes to cope with energy demands and critically influences neuronal death and disease progression. Aberrant glial cells detected in the spinal cord of diseased animals are characterized by increased proliferation rate and reduced mitochondrial bioenergetics. These features can be compared with cancer cell behavior of adapting to nutrient microenvironment by altering energy metabolism, a concept known as metabolic reprogramming. We focus on data that suggest that aberrant glial cells in ALS undergo metabolic reprogramming and profound changes in glial mitochondrial activity, which are associated with motor neuron death in ALS. This review article emphasizes on the association between metabolic reprogramming and glial reactivity, bringing new paradigms from the area of cancer research into neurodegenerative diseases. Targeting glial mitochondrial function and metabolic reprogramming may result in promising therapeutic strategies for ALS.

scholarly journals Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

2011 ◽  
Vol 301 (5) ◽  
pp. H2093-H2101 ◽  
Author(s):  
Baptiste Kurtz ◽  
Helene B. Thibault ◽  
Michael J. Raher ◽  
John R. Popovich ◽  
Sharon Cawley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Insulin Resistance ◽  
Mitochondrial Respiration ◽  
Pressure Overload ◽  
Lv Remodeling ◽  
Stress Levels ◽  
Nitric Oxide Synthase 3 ◽  
And Function ◽  
Oxide Synthase

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.

scholarly journals Sepiapterin Improves Vascular Reactivity and Insulin-Stimulated Glucose in Wistar Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
A. C. Keller ◽  
L. A. Knaub ◽  
R. L. Scalzo ◽  
S. E. Hull ◽  
A. E. Johnston ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Wistar Rats ◽  
Vascular Reactivity ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Respiratory Control ◽  
Mitochondrial Activity ◽  
Insulin Tolerance ◽  
Male Wistar Rats ◽  
Endothelial Nitric Oxide

In the vasculature, sedentary behavior leads to endothelial abnormalities, resulting in elevated cardiovascular disease risk. Endothelial nitric oxide synthase (eNOS) aberrations characterize endothelial dysfunction; eNOS also regulates mitochondrial function. We hypothesized that sepiapterin (a precursor to eNOS cofactor tetrahydrobiopterin (BH4)) supplementation would improve endothelium-dependent vascular relaxation in sedentary animals via modulation of NOS function and mitochondrial activity. Sedentary male Wistar rats were fed ad libitum for a total of 10 weeks. Sepiapterin was administered in diet during the final 5 weeks. Intraperitoneal insulin and glucose tolerance tests (IP-ITT/IP-GTT) were conducted at baseline and endpoint. Aorta was assessed for vasoreactivity and mitochondrial respiration. Insulin tolerance, determined by IP-ITT, significantly improved in rats treated with sepiapterin (p<0.05, interaction of time and treatment). Acetylcholine- (ACh-) driven vasodilation was significantly greater in aorta from sepiapterin-treated rats as compared with control (76.4% versus 54.9% of phenylephrine contraction at 20 μM ACh, p<0.05). Sepiapterin treatment resulted in significantly elevated state 3 (9.00 oxygen pmol/sec∗mg versus 8.17 oxygen pmol/sec∗mg, p<0.05) and 4 (7.28 oxygen pmol/sec∗mg versus 5.86 oxygen pmol/sec∗mg, p<0.05) aortic mitochondrial respiration with significantly lower respiratory control ratio (p<0.05) during octanoylcarnitine-driven respiration. Vasodilation and insulin sensitivity were improved through targeting NOS via sepiapterin supplementation.

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