br Introduction br Mitochondrial dysfunction and

Introduction
Mitochondrial dysfunction and cancer
Lactate and succinate as oncometabolites
Intracellular actions of lactate and succinate as tumor promoters
Cell-surface receptors for lactate and succinate and their role in cancer
GPR109A as the receptor for butyrate and β-hydroxybutyrate and its connection to cancer
SIRT3 and its link to the metabolite receptors and cancer Mitochondrial function is fundamentally linked to lactate, succinate, and β-hydroxybutyrate. Deficiency of mitochondrial function impacts circulating levels of all three metabolites. SIRT3 is the principal NAD+-dependent deacetylase critical for optimal mitochondrial function. The enzymatic activity of SIRT3 is responsible for the maintenance of optimal activities of pyruvate dehydrogenase, succinate dehydrogenase, and HMGCS2, which is essential for normal oxidation of lactate and succinate and for normal production of β-hydroxybutyrate. As lactate and succinate promote cancer via their respective receptors GPR81 and GPR91 whereas β-hydroxybutyrate protects against cancer via its receptor GPR109A, SIRT3 functions are associated with tumor suppression. SIRT3 deficiency elicits the opposite effects by increasing cellular and circulating levels of the tumor promoters lactate and succinate and by compromising the generation of the tumor suppressor β-hydroxybutyrate. The functional link between SIRT3 and the metabolite receptors GPR81, GPR91, and GPR109A highlights the potential of SIRT3 as a drug target for cancer prevention and cancer treatment.
Conclusions
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Acknowledgements This work was supported by the National Institutes of Health grant CA190710 and by the Welch Endowed Chair in Biochemistry, Grant No. BI-0028, at Texas Tech University Health Sciences Center.
Introduction Many nutrients and intermediates of Y-27632 metabolism are not only carriers of energy but also function as signaling molecules which modulate metabolic, immune, and other functions in the mammalian organism by activating specific receptors. While nuclear receptors have long been known to play important roles in mediating effects of metabolites 1, 2, more recently various G protein-coupled receptors have also been shown to be activated by metabolic intermediates [3]. Prominent examples are the hydroxy-carboxylic acid (HCA) receptors. The HCA receptor family consists of three members, HCA1, HCA2, and HCA3, also known as GPR81, GPR109A, and GPR109B, respectively, which are encoded by closely related genes [4]. The physiological ligands of HCA receptors are key metabolic intermediates whose local and systemic levels reflect particular metabolic states. Lactic acid, the end product of glycolysis, activates HCA1, whereas the ketone body 3-hydroxy-butyric acid [β-hydroxybutyrate (β-HB)] and the β-oxidation intermediate 3-hydroxy-octanoic acid activate HCA2 and HCA3, respectively. In addition, HCA2 is also activated by butyric acid. HCA receptors have relatively low affinities for their natural ligands, however, in some cases, synthetic ligands with increased affinity have been developed [4]. In addition, drugs such as nicotinic acid and dimethyl fumarate (DMF) have been shown to exert at least part of their pharmacological activity through the receptor HCA24, 5, 6. The pharmacological properties of HCA receptors have recently been summarized by several reviews 4, 7. This review will focus on the physiological and pathophysiological functions, as well as on the therapeutic potential of this receptor family.
General Properties of HCA Receptors The genes encoding the three HCA receptors are located next to each other on human chromosome 12 and mouse chromosome 5. HCA1 is the phylogenetically oldest receptor, found already in fish [8]. By contrast, functionally active HCA2 receptors appear to be restricted to mammals, and the HCA3 receptor has only been found in higher primates [9]. Consistent with the close genetic relationship of the genes encoding the three receptors, their main physiological ligands also show structural similarity, as they are all hydroxylated carboxylic acids. With regard to their downstream signaling, all HCA receptors are coupled to Gi-type G proteins 10, 11, 12, 13, 14, 15, 16.