Orphan detectors of metabolism

Hebert, Steven C.

doi:10.1038/429143a

Cited by 43 publications

(30 citation statements)

References 16 publications

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“…21,22 In addition, accumulation of succinate also occurs extracellularly in the peripheral tissues during specific pathophysiological states when the energy and oxygen supply/demand are unbalanced. 29 Toma et al have also demonstrated there is succinate accumulation in diabetic kidney tissues and in the urine. 30 Their results suggested that hyperglycemia is associated with further, remarkable reductions in renal oxygen tension and mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 95%

Succinate Increases in the Vitreous Fluid of Patients With Active Proliferative Diabetic Retinopathy

Matsumoto

Suzuma

Maki

et al. 2012

American Journal of Ophthalmology

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Section: Discussionmentioning

confidence: 95%

Succinate Increases in the Vitreous Fluid of Patients With Active Proliferative Diabetic Retinopathy

Matsumoto

Suzuma

Maki

et al. 2012

American Journal of Ophthalmology

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“…However, succinate can accumulate extracellularly in peripheral tissues in certain pathophysiological states when energy and oxygen supply/demand are out of balance (5). Although, it is not feasible to measure succinate levels in the JGA interstitium, conditions of the renal cortical environment seem to be favorable for local succinate accumulation.…”

Section: Discussionmentioning

confidence: 99%

Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney

Toma

Kang²,

Sipos³

et al. 2008

J. Clin. Invest.

211

277

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Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein-coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca 2+ , the production of NO and prostaglandin (PGE 2 ), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.

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“…Succinate has been shown to be a natural ligand for an orphan receptor highly expressed in kidneys with a pro-hypertensive effect involving the renninangiotensin system, while α-ketoglutarate is a ligand for a homologous receptor (He et al, 2004). It has been suggested that mitochondrial dysfunction, caused by an imbalance of energy supply and demand or altered metabolism of citric acid cycle intermediates may result in the release of citric acid cycle intermediates (Hebert, 2004), albeit the underlying mechanisms have not as yet been fully elucidated. Nevertheless, it is of interest to point out that aging animals suffer from metabolic diseases such as hypertension, atherosclerosis and diabetes, which may, in part, be affected by an age-associated alteration of the citric acid cycle and, consequently, intermediates acting as signaling molecules.…”

Section: Discussionmentioning

confidence: 99%

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice

Yarian

Toroser

Sohal

2006

Mechanisms of Ageing and Development

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The activities of the citric acid cycle enzymes were determined in mitochondria isolated from kidneys of relatively young, middle age, and old mice. Aconitase exhibited the most significant decrease in activity with age. The activity of α-ketoglutarate dehydrogenase exhibited a modest decrease in activity, while NADP + -isocitrate dehydrogenase (NADP + -ICD) activity increased moderately with age. Activities of citrate synthase, NAD + -isocitrate dehydrogenase (NAD + -ICD), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SD), fumarase (FUM), and malate dehydrogenase (MD) were not affected. The molar ratio of the intra-mitochondrial redox indicator, NADPH:NADP + , was higher in young compared to old animals, while the NADH:NAD + molar ratio remained unchanged. It is suggested that an age-related decrease in aconitase activity along with relatively subtle alterations in activities of some other citric acid cycle enzymes are likely to contribute to a decline in the overall efficiency of mitochondrial bioenergetics. The biological consequences of such alterations include age-related fluctuations in the citric acid cycle intermediates, which are precursors of protein synthesis, activators of fatty acid synthesis, and can also act as ligands for orphan G-protein coupled receptors.

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Orphan detectors of metabolism

Cited by 43 publications

References 16 publications

Succinate Increases in the Vitreous Fluid of Patients With Active Proliferative Diabetic Retinopathy

Succinate Increases in the Vitreous Fluid of Patients With Active Proliferative Diabetic Retinopathy

Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice

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