Mitochondrial TCA cycle intermediates regulate body fluid and acid-base balance

Peti‐Peterdi, Janos

doi:10.1172/jci68095

Cited by 17 publications

(16 citation statements)

References 16 publications

(26 reference statements)

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“…These results also suggested that GPR99-mediated distal NaCl reabsorption is required to compensate for the altered proximal reabsorption of salt under a body acid-base challenge (6). This novel α-ketoglutarate/GPR99 paracrine mechanism may act along with the related and above-described succinate/GPR91 pathway to maintain body fluid, electrolyte, and acid-base homeostasis (39). …”

Section: Mitochondrial Citric Acid Cycle Intermediates and Their Gpcrsmentioning

confidence: 99%

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Regulation of Vascular and Renal Function by Metabolite Receptors

Peti‐Peterdi

Kishore

Pluznick

2016

Annu. Rev. Physiol.

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To maintain metabolic homeostasis, the body must be able to monitor the concentration of a large number of substances, including metabolites, in real time and to use that information to regulate the activities of different metabolic pathways. Such regulation is achieved by the presence of sensors, termed metabolite receptors, in various tissues and cells of the body, which in turn convey the information to appropriate regulatory or positive or negative feedback systems. In this review, we cover the unique roles of metabolite receptors in renal and vascular function. These receptors play a wide variety of important roles in maintaining various aspects of homeostasis—from salt and water balance to metabolism—by sensing metabolites from a wide variety of sources. We discuss the role of metabolite sensors in sensing metabolites generated locally, metabolites generated at distant tissues or organs, or even metabolites generated by resident microbes. Metabolite receptors are also involved in various pathophysiological conditions and are being recognized as potential targets for new drugs. By highlighting three receptor families—(a) citric acid cycle intermediate receptors, (b) purinergic receptors, and (c) short-chain fatty acid receptors—we emphasize the unique and important roles that these receptors play in renal and vascular physiology and pathophysiology.

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Section: Mitochondrial Citric Acid Cycle Intermediates and Their Gpcrsmentioning

confidence: 99%

“…Abbreviations: αKG, α-ketoglutarate; CD, collecting duct; COX-2; cyclooxygenase-2; CNT, connecting tubule; IC, intercalated cell; JGA, juxtaglomerular apparatus; JGC, juxtaglomerular cell; PGE 2 , prostaglandin E 2 ; RAS, renin-angiotensin system. Adapted with permission from Peti-Peterdi (39). …”

Section: Figurementioning

confidence: 99%

Regulation of Vascular and Renal Function by Metabolite Receptors

Peti‐Peterdi

Kishore

Pluznick

2016

Annu. Rev. Physiol.

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“…Building on this finding, a study in 2013 (Tokonami et al 2013) showed that these changes in a-ketoglutarate concentration are sensed by Gpr99, which is expressed in the intercalated cells later on in the connecting tubule and connecting duct (Tokonami et al 2013, Diehl et al 2016. Thus, a-ketoglutarate signalling to its receptor later on in the nephron serves as an intrarenal and intratubule paracrine signalling mechanism (Allison 2013, Peti-Peterdi 2013, Tokonami et al 2013, Morla et al 2016. Intercalated cells are critical in the control of acid/base balance, and a-ketoglutarate signalling to Gpr99 in the intercalated cells is a mechanism to instruct the intercalated cells to activate pendrin and regulate HCO 3 À to combat the alkalosis.…”

Section: Gpr91 (Adopted Name: Sucnr1)mentioning

confidence: 98%

“…). Thus, α‐ketoglutarate signalling to its receptor later on in the nephron serves as an intrarenal and intratubule paracrine signalling mechanism (Allison , Peti‐Peterdi , Tokonami et al . , Morla et al .…”

Section: Gpr99 (Adopted Name: Oxgr1)mentioning

confidence: 99%

Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Rajkumar

Pluznick

2016

Acta Physiologica

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Recent studies have shown that orphan GPCRs of the GPR family are utilized as specialized chemosensors in various tissues to detect metabolites, and in turn to activate downstream pathways which regulate systemic homeostasis. These studies often find that such metabolites are generated by well-known metabolic pathways, implying that known metabolites and chemicals may perform novel functions. In this review, we summarize recent findings highlighting the role of deorphanized GPRs in renal development and function. Understanding the role of these receptors is critical in gaining insights into mechanisms that regulate renal function both in health and in disease.

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“…The immediate outcome of deranged energy processing is the reduced ability to switch from one fuel source (e.g., glucose) to another (e.g., fatty acids), resulting in altered flux between glycolytic pathways and oxidative capacity within cells and tissues. The recognition that mitochondria may play a central role in disease has renewed interest in the Randle cycle and the Warburg effect in the pathogenesis of common diseases [5,6], and may be relevant because the inefficient use of glucose, lipotoxicity, and decreased fat oxidation are key mechanisms to explain most noncommunicable diseases [7,8]. Consequently, the pharmacologic modulation of mitochondrial function mimicking the effect of exercise and/or caloric restriction may be an attractive therapeutic strategy [9,10].…”

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confidence: 99%

Exploring the Process of Energy Generation in Pathophysiology by Targeted Metabolomics: Performance of a Simple and Quantitative Method

Riera-Borrull

Rodríguez-Gallego

Hernández-Aguilera

et al. 2015

J. Am. Soc. Mass Spectrom.

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Abstract. Abnormalities in mitochondrial metabolism and regulation of energy balance contribute to human diseases. The consequences of high fat and other nutrient intake, and the resulting acquired mitochondrial dysfunction, are essential to fully understand common disorders, including obesity, cancer, and atherosclerosis. To simultaneously and noninvasively measure and quantify indirect markers of mitochondrial function, we have developed a method based on gas chromatography coupled to quadrupole-time of flight mass spectrometry and an electron ionization interface, and validated the system using plasma from patients with peripheral artery disease, human cancer cells, and mouse tissues. This approach was used to increase sensibility in the measurement of a wide dynamic range and chemical diversity of multiple intermediate metabolites used in energy metabolism. We demonstrate that our targeted metabolomics method allows for quick and accurate identification and quantification of molecules, including the measurement of small yet significant biological changes in experimental samples. The apparently low process variability required for its performance in plasma, cell lysates, and tissues allowed a rapid identification of correlations between interconnected pathways. Our results suggest that delineating the process of energy generation by targeted metabolomics can be a valid surrogate for predicting mitochondrial dysfunction in biological samples. Importantly, when used in plasma, targeted metabolomics should be viewed as a robust and noninvasive source of biomarkers in specific pathophysiological scenarios.

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Mitochondrial TCA cycle intermediates regulate body fluid and acid-base balance

Cited by 17 publications

References 16 publications

Regulation of Vascular and Renal Function by Metabolite Receptors

Regulation of Vascular and Renal Function by Metabolite Receptors

Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Exploring the Process of Energy Generation in Pathophysiology by Targeted Metabolomics: Performance of a Simple and Quantitative Method

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