Skip to main content
SpringerLink
Log in

Leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Cardiac pathology including hypertrophy has been associated with an imbalance between mitochondrial fission and fusion. Generally, well-balanced mitochondrial fission and fusion are essential for proper functions of mitochondria. Leptin is a 16-kDa appetite-suppressing protein which has been shown to induce cardiomyocyte hypertrophy. In the present study, we determined whether leptin can influence mitochondrial fission or fusion and whether this can be related to its hypertrophic effect. Cardiomyocytes treated for 24 h with 3.1 nM leptin (50 ng/ml), a concentration representing plasma levels in obese individuals, demonstrated an increase in surface area and a significant 1.6-fold increase in the expression of the β-myosin heavy chain. Mitochondrial staining with MitoTracker Green dye showed elongated structures in control cells with an average length of 4.5 µm. Leptin produced a time-dependent increase in mitochondrial fragmentation with decreasing mitochondrial length. The hypertrophic response to leptin was also associated with increased protein levels of the mitochondrial fission protein dynamin-related protein1 (Drp1) although gene expression of Drp1 was unaffected possibly suggesting post-translational modifications of Drp1. Indeed, leptin treatment was associated with decreased levels of phosphorylated Drp1 and increased translocation of Drp1 to the mitochondria thereby demonstrating a pro-fission effect of leptin. As calcineurin may dephosphorylate Drp1, we determined the effect of a calcineurin inhibitor, FK506, which prevented leptin-induced hypertrophy as well as mitochondrial fission and mitochondrial dysfunction. In conclusion, our data show that leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission via a calcineurin-mediated pathway. The ability of leptin to stimulate mitochondrial fission may be important in understanding the role of this protein in cardiac pathology especially that related to mitochondrial dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Cammisotto PG, Bukowiecki LJ, Deshaies Y, Bendayan M (2006) Leptin biosynthetic pathway in white adipocytes. Biochem Cell Biol 84:207–214

    Article  CAS  PubMed  Google Scholar 

  2. Xie L, O’Reilly CP, Chape SK, Mora S (2008) Adiponectin and leptin are secreted through distinct trafficking pathways in adipocytes. Biochim Biophys Acta 1782:99–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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:H441–H446

    Article  CAS  Google Scholar 

  4. Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M (2003) The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res 93:277–279

    Article  CAS  PubMed  Google Scholar 

  5. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295

    Article  CAS  PubMed  Google Scholar 

  6. Perego L, Pizzocri P, Corradi D, Maisano F, Paganelli M, Fiorina P, Barbieri M, Morabito A, Paolisso G, Folli F, Pontiroli AE (2005) Circulating leptin correlates with left ventricular mass in morbid (Grade III) obesity before and after weight loss induced by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy. J Clin Endocrinol Metab 90:4087–4093

    Article  CAS  PubMed  Google Scholar 

  7. Schulze PC, Kratzsch J, Linke A, Schoene N, Adams V, Gielen S, Erbs S, Moebius-Winkler S, Schuler G (2003) Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure. Eur J Heart Fail 5:33–40

    Article  PubMed  Google Scholar 

  8. Toth MJ, Gottlieb SS, Fisher ML, Ryan AS, Nicklas BJ, Poehlman ET (1997) Plasma leptin concentrations and energy expenditure in heart failure patients. Metabolism 46:450–453

    Article  CAS  PubMed  Google Scholar 

  9. Fruhbeck G (2006) Intracellular signaling pathways activated by leptin. Biochem J 393:7–20

    Article  CAS  PubMed  Google Scholar 

  10. Yamashita T, Murakami T, Otani S, Kuwajima M, Shima K (1998) Leptin receptor signal transduction:OBRa and OBRb of fa type. Biochem Biophys Res Commun 246:752–759

    Article  CAS  PubMed  Google Scholar 

  11. Gan XT, Zhao G, Huang CX, Rowe AC, Purdham DM, Karmazyn M (2013) Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes:regulation by leptin and its contribution to leptin-induced hypertrophy. PLoS ONE 8:e74235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rajapurohitam V, Izaddoustdar F, Martinez-Abundis E, Karmazyn M (2012) Leptin-induced cardiomyocyte hypertrophy reveals both calcium-dependent and calcium-independent/RhoA-dependent calcineurin activation and NFAT nuclear translocation. Cell Signal 24:2283–2290

    Article  CAS  PubMed  Google Scholar 

  13. Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, Luo JD (2004) Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 110:1269–1275

    Article  CAS  PubMed  Google Scholar 

  14. Zeidan A, Javadov S, Chakrabarti S, Karmazyn M (2008) Leptin-induced cardiomyocyte hypertrophy involves selective caveolae and RhoA/ROCK-dependent p38 MAPK translocation to nuclei. Cardiovasc Res 77:64–72

    Article  CAS  PubMed  Google Scholar 

  15. Ashrafian H, Docherty L, Leo V, Towlson C, Neilan M, Steeples V, Lygate CA, Hough T, Townsend S, Williams D, Wells S, Norris D, Glyn-Jones S, Land J, Barbaric I, Lalanne Z, Denny P, Szumska D, Bhattacharya S, Griffin JL, Hargreaves I, Fernandez-Fuentes N, Cheeseman M, Watkins H, Dear TN (2010) A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy. PLoS Genet 6:e1001000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Watanabe T, Saotome M, Nobuhara M, Sakamoto A, Urushida T, Katoh H, Satoh H, Funaki M, Hayashi H (2014) Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance. Exp Cell Res 323:314–325

    Article  CAS  PubMed  Google Scholar 

  17. Dezfulian C, Shiva S, Alekseyenko A, Pendyal A, Beiser DG, Munasinghe JP, Anderson SA, Chesley CF, Hoek TLV, Gladwin MT (2009) Nitrite therapy after cardiac arrest reduces reactive oxygen species generation improves cardiac and neurological function and enhances survival via reversible inhibition of mitochondrial complex I. Circulation 120:897–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cocheme HM, Murphy MP, Dominiczak AF (2009) Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 54:322–328

    Article  CAS  PubMed  Google Scholar 

  19. Griffiths EJ, Halestrap AP (1993) Protection by cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 25:1461–1469

    Article  CAS  PubMed  Google Scholar 

  20. Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori R, Ikeuchi M, Kubota T, Sunagawa K, Hasegawa Y, Kurihara T, Oikawa S, Kinugawa S, Tsutsui H (2006) Overexpression of mitochondria peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 113:1779–1786

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879

    Article  CAS  PubMed  Google Scholar 

  23. Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JK, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo J 27:433–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jheng HF, Tsai PJ, Guo SM, Kuo LH, Chang CS, Su IJ, Chang CR, Tsai YS (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32:309–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pennanen C, Parra V, Lopez-Crisosto C, Morales PE, del Campo A, Gutierrez T, Rivera-Mejias P, Kuzmicic J, Chiong M, Zorzano A, Rothermel BA, Lavandero S (2014) Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. J Cell Sci 127:2659–2671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Molina AJA, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A, Walzer G, Twig G, Katz S, Corkey BE, Shirihai OS (2009) Mitochondrial networking protects b-cells from nutrient-induced apoptosis. Diabetes 58:2303–2315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, Banathy A, Morrow E, Ryan JJ, Archer SL (2014) Dynamin-related protein (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. FASEB J 28:316–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, Thenappan T, Piao L, Zhang HJ, Pogoriler J, Chen Y, Morrow E, Weir EK, Rehman J, Archer SL (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110:1484–1497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cereghetti GM, Stangherlin A, de Brito OM, Chang CR, Blakstone C, Bernardi P, Scorrano L (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci USA 105:15803–15808

    Article  PubMed  Google Scholar 

  30. Wai T, Garcia-Prieto J, Baker MJ, Merkwirth C, Benit P, Rustin P, Ruperez FJ, Barbas C, Ibanez B, Langer T (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116

    Article  CAS  PubMed  Google Scholar 

  31. Song M, Mihara K, Chen Y, Scorrano L, Dorn GW (2015) Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Javadov S, Rajapurohitam V, Kilic A, Zeidan A, Choi A, Karmazyn M (2009) Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3β-dependent attenuation of mitochondrial dysfunction. J Mol Cell Cardiol 46:998–1007

    Article  CAS  PubMed  Google Scholar 

  34. Mikusova A, Kralova E, Tylkova L, Novotova M, Stankovicoya T (2009) Myocardial remodeling induced by repeated low doses of isoproterenol. Can J Physiol Pharmacol 87:641–651

    Article  CAS  PubMed  Google Scholar 

  35. Banerjee P, Chander V, Bandyopadhyay A (2015) Balancing functions of annexin A6 maintain equilibrium between hypertrophy and apoptosis in cardiomyocytes. Cell Death Dis 6:e1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yin W, Li R, Feng X, Kang YJ (2018) The involvement of cytochrome c oxidase in mitochondrial fusion in primary cultures of neonatal cardiomyocytes. Cardiovasc Toxicol 8:365–373

    Article  CAS  Google Scholar 

  37. De Windt LJ, Lim HW, Bueno OF, Liang Q, Delling U, Braz JC, Glascock BJ, Kimball TF, del Monte F, Hajjar RJ, Molkentin JD (2001) Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98:3322–3327

    Article  PubMed  Google Scholar 

  38. Zou Y, Hiroi Y, Uozumi H, Takimoto E, Toko H, Zhu W, Kudoh S, Mizukami M, Shimoyama M, Shibasaki F, Nagai R, Yazaki Y, Komuro I (2001) Calcineurin plays a clinical role in the development of pressure overload-induced cardiac hypertrophy. Circulation 104:97–101

    Article  CAS  PubMed  Google Scholar 

  39. Zeidan A, Purdham DM, Rajapurohitam V, Javadov S, Chakrabarti S, Karmazyn M (2005) Leptin induces vascular smooth cell hypertrophy through angiotensin II- and endothelin-1-dependent mechanisms and mediates stretch-induced hypertrophy. J Pharmacol Exp Therap 315:1075–1084

    Article  CAS  Google Scholar 

  40. Lee MPS, Orlov D, Sweeney G (2005) Leptin induces rat glomerular mesangial cell hypertrophy, but does not regulate hyperplasia or apoptosis. Int J Obes 29:1395–1401

    Article  CAS  Google Scholar 

  41. Hou N, Luo MS, Liu SM, Zhang HN, Xiao Q, Sun P, Zhang GS, Luo JD, Chen MS (2010) Leptin induces hypertrophy through activating the peroxisome proliferator-activated receptor α pathway in cultured neonatal rat cardiomyocytes. Clin Exp Pharmacol Physiol 37:1087–1095

    Article  CAS  PubMed  Google Scholar 

  42. Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, D’Errico A, Marfella R, Carella C, de Divitiis O, Varricchio M (2001) Plasma leptin concentration, insulin sensitivity, and 24-hour ambulatory blood pressure and left ventricular geometry. Am J Hypertens 14:114–120

    Article  CAS  PubMed  Google Scholar 

  43. Romero-Corral A, Sierra-Johnson J, Lopez-Jimenez F, Thomas RJ, Singh P, Hoffmann M, Okcay A, Korinek J, Wolk R, Somes WK (2008) Relationships between leptin and C-reactive protein with cardiovascular disease in the adult general population. Nat Clin Pract Cardiovasc Med 5:418–425

    Article  CAS  PubMed  Google Scholar 

  44. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, Matsuoka N, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Nakao K (2000) Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 105:1243–1252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Leyva F, Godsland IF, Ghatei M, Proudler AJ, Aldis S, Walton C, Bloom S, Stevenson JC (1998) Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol 18:928–933

    Article  CAS  PubMed  Google Scholar 

  46. Chen L, Gong Q, Stice JP, Knowlton AA (2009) Mitochondrial OPA1, apoptosis and heart failure. Cardiovasc Res 84:91–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alaimo A, Gorojoh RM, Beauquis J, Munoz MJ, Saravia F, Kotler ML (2014) Deregulation of mitochondria-shaping proteins Opa-1 and Drp-1 in manganese-induced apoptosis. PLos ONE 9:e91848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Longo DL (2013) Mitochondrial dynamics-mitochondrial fission and fusion in human diseases. N Engl J Med 369:2236–2251

    Article  CAS  Google Scholar 

  49. Dorn GWII (2013) Mitochondrial dynamics in heart disease. Biochim Biophys Acta 1833:233–241

    Article  CAS  PubMed  Google Scholar 

  50. Baandrup U, Florio RA, Roters F, Olsen EGJ (1981) Electron microscopic investigation of endomyocardial biopsy samples in hypertrophy and cardiomyocytes: a semiquantitative study in 48 patients. Circulation 63:1289–1298

    Article  CAS  PubMed  Google Scholar 

  51. Harder Z, Zunino R, McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14:340–345

    Article  CAS  PubMed  Google Scholar 

  52. Karbowski M, Neutzner A, Youle RJ (2007) The mitochondrial E3 ubiquitin ligase March5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178:71–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nakamura T, Cieplak P, Cho DH, Godzik A, Lipton SA (2010) S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration. Mitochondrion 10:573–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Manukyan I, Galatioto J, Mascareno E, Bhaduri S, Siddiqui MA (2010) Cross-talk between calcineurin/NFAT and Jak/STAT signalling induces cardioprotective αB-crystallin gene expression in response to hypertrophic stimuli. J Cell Mol Med 14:1707–1716

    Article  CAS  PubMed  Google Scholar 

  55. 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

    Article  CAS  PubMed  Google Scholar 

  56. Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1α. Cardiovasc Res 79:208–217

    Article  CAS  PubMed  Google Scholar 

  57. Rimbaud S, Garnier A, Ventura-Clapier R (2009) Mitochondrial biogenesis in cardiac pathophysiology. Pharmacol Rep 61:131–138

    Article  CAS  PubMed  Google Scholar 

  58. Pfluger PT, Kabra DG, Aichler M, Schriever SC, Pfuhlmann K, García VC, Lehti M, Weber J, Kutschke M, Rozman J, Elrod JW, Hevener AL, Feuchtinger A, Hrabě de Angelis M, Walch A, Rollmann SM, Aronow BJ, Müller TD, Perez-Tilve D, Jastroch M, De Luca M, Molkentin JD, Tschöp MH (2015) Calcineurin links mitochondrial elongation with energy metabolism. Cell Metab 22:838–850

    Article  CAS  PubMed  Google Scholar 

  59. Martinez-Abundis E, Rajapurohitam V, Gertler A, Karmazyn M (2015) Identification of functional leptin receptors expressed in ventricular mitochondria. Mol Cell Biochem 408:155–162

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a Grant from the Canadian Institutes of Health Research (MOP 62764). M Karmazyn held a Tier 1 Canada Research Chair in Experimental Cardiology (2004–2016).

Author information

Author notes

  1. Chian Ju Jong

    Present address: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

  2. Morris Karmazyn: Retired

Authors and Affiliations

  1. University of Western Ontario, London, ON, N6A 5C1, Canada

    Chian Ju Jong, Justin Yeung, Emily Tseung & Morris Karmazyn

Authors
  1. Chian Ju Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Justin Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emily Tseung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morris Karmazyn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Morris Karmazyn.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jong, C.J., Yeung, J., Tseung, E. et al. Leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission. Mol Cell Biochem 454, 33–44 (2019). https://doi.org/10.1007/s11010-018-3450-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3450-5

Keywords

Search

Navigation