Abstract
Leptin is a 16 kDa pro-satiety peptide produced primarily not only by white adipocytes but also by numerous other tissues including the heart. Circulating leptin exerts its effect through specific receptors, although its principle actions are dependent on the activation of the long form of the leptin receptor, termed OBRb. As leptin is also produced within the cardiomyocyte, we hypothesized that the peptide can also exert effects by targeting intracellular sites. Accordingly, we determined whether cardiac mitochondria express functional leptin receptors. The presence of mitochondrial OBRb was identified through Western blotting of isolated mitochondria, immunofluorescence as well as immunogold labeling with electron microscopy. Although leptin had no direct effect on mitochondrial integrity, it profoundly enhanced the ability of calcium to induce mitochondrial swelling, an effect partially reversed by an OBR antagonist. 24 h exposure to leptin (50 ng/ml) was without effect on mitochondria in cultured neonatal rat ventricular myocytes in contrast to leptin tagged with a 10 amino acid membrane translocation sequence which significantly induced mitochondrial permeability transition pore opening, whereas both leptins produced a hypertrophic response. Our results therefore show that mitochondria express functional OBR which may be of importance toward understanding the role of intracellularly derived leptin in cardiac physiology and pathology.
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Dardeno TA, Chou SH, Moon HS, Chamberland JP, Fiorenza CG, Mantzoros CS (2010) Leptin in human physiology and therapeutics. Front Neuroendocrinol 31:377–393
Purdham DM, Zou MX, Rajapurohitam V, Karmazyn M (2004) Rat heart is a site of leptin production and action. Am J Physiol Heart Circ Physiol 287:H2877–H2884
Rajapurohitam V, Javadov S, Purdham DM, Kirshenbaum LA, Karmazyn M (2006) An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. J Mol Cel. Cardiol 41:265–274
Northcott JM, Yeganeh A, Taylor CG, Zahradka P, Wigle JT (2012) Adipokines and the cardiovascular system: mechanisms mediating health and disease. Can J Physiol Pharmacol 90:1029–1059
Karmazyn M, Rajapurohitam V (2014) Leptin as a cardiac pro-hypertrophic factor and its potential role in the development of heart failure. Curr Pharm Des 20:646–651
Martinez-Abundis E, Rajapurohitam V, Haist JV, Gan XT, Karmazyn M (2012) The obesity-related peptide leptin sensitizes cardiac mitochondria to calcium-induced permeability transition pore opening and apoptosis. PLoS One 7:e41612
Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, Smith BJ, Burks TN, Cohn RD, Fedarko NS, Carey RM, O’Rourke B, Walston JD (2011) Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci USA 108:14849–14854
Chen JQ, Delannoy M, Cooke C, Yager JD (2004) Mitochondrial localization of ERα and ERβ in human MCF7 cells. Am J Physiol Endocrinol Metab 286:E1011–E1022
Javadov S, Rajapurohitam V, Kilić A, Hunter JC, Zeidan A, Said Faruq N, Escobales N, Karmazyn M (2011) Expression of mitochondrial fusion-fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition. Basic Res Cardiol 106:99–109
Banks AS, Davis SM, Bates SH, Myers MG Jr (2000) Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 275:14563–14572
Javadov S, Karmazyn M (2007) Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem 20:1–22
Savard M, Barbaz D, Bélanger S, Müller-Ester W, Bkaily G, D’orléans-Juste P, Coté J, Bovenzi V, Gobeil F Jr (2008) Expression of endogenous nuclear bradykinin B2 receptors mediating signaling in immediate early gene activation. J Cell Physiol 216:234–244
Bkaily G, Avedanian L, Al-Khoury J, Ahmarani L, Perreault C, Jacques D (2012) Receptors and ionic transporters in nuclear membranes: new targets for therapeutical pharmacological interventions. Can J Physiol Pharmacol 90:953–965
Bkaily G, Al-Khoury J, Jacques D (2014) Nuclear membranes GPCRs: implication in cardiovascular health and diseases. Curr Vasc Pharmacol 12:215–222
Acknowledgments
This work was supported by a grant from the Canadian Institutes of Health Research (MOP 62764). M Karmazyn holds a Tier 1 Canada Research Chair in Experimental Cardiology.
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Martinez-Abundis, E., Rajapurohitam, V., Gertler, A. et al. Identification of functional leptin receptors expressed in ventricular mitochondria. Mol Cell Biochem 408, 155–162 (2015). https://doi.org/10.1007/s11010-015-2491-2
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DOI: https://doi.org/10.1007/s11010-015-2491-2