Advertisement

Role of Mitochondrial Dysfunction in Hypertension and Obesity

  • Vicente LaheraEmail author
  • Natalia de las Heras
  • Antonio López-Farré
  • Walter Manucha
  • León Ferder
Hypertension and Obesity (E Reisin, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and Obesity

Abstract

Mitochondria are essential for the maintenance of normal physiological function of tissue cells. Mitochondria are subject to dynamic processes in order to establish a control system related to survival or cell death and adaptation to changes in the metabolic environment of cells. Mitochondrial dynamics includes fusion and fission processes, biogenesis, and mitophagy. Modifications of mitochondrial dynamics in organs involved in energy metabolism such as the pancreas, liver, skeletal muscle, and white adipose tissue could be of relevance for the development of insulin resistance, obesity, and type 2 diabetes. Mitochondrial dynamics and the factors involved in its regulation are also critical for neuronal development, survival, and function. Modifications in mitochondrial dynamics in either agouti-related peptide (AgRP) or pro-opiomelanocortin (POMC), circuits which regulates feeding behavior, are related to changes of food intake, energy balance, and obesity development. Activation of the sympathetic nervous system has been considered as a crucial point in the pathogenesis of hypertension among obese individuals and it also plays a key role in cardiac remodeling. Hypertension-related cardiac hypertrophy is associated with changes in metabolic substrate utilization, dysfunction of the electron transport chain, and ATP synthesis. Alterations in both mitochondrial dynamics and ROS production have been associated with endothelial dysfunction, development of hypertension, and cardiac hypertrophy. Finally, it might be postulated that alterations of mitochondrial dynamics in white adipose tissue could contribute to the development and maintenance of hypertension in obesity situations through leptin overproduction. Leptin, together with insulin, will induce activation of sympathetic nervous system with consequences at renal, vascular, and cardiac levels, driving to sodium retention, hypertension, and left ventricular hypertrophy. Moreover, both leptin and insulin will induce mitochondrial alterations into arcuate nucleus leading to signals driving to increased food intake and reduced energy expenditure. This, in turn would perpetuate white adipose tissue excess and its well-known metabolic and cardiovascular consequences.

Keywords

Mitochondrial dynamics Mitochondrial dysfunction Hypertension Obesity 

Notes

Authors’ Contributions

All authors contributed to the manuscript writing. The authors have read and approved the final version of the manuscript.

Compliance with Ethical Standards

Conflict of Interest

Drs. Lahera, de las Heras, López-Farré, Manucha, and Ferder declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Logan DC. The mitochondrial compartment. J Exp Bot. 2006;57(6):1225–43.CrossRefPubMedGoogle Scholar
  2. 2.
    Wallace DC. The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene. 2005;18(354):169–80.CrossRefGoogle Scholar
  3. 3.
    Chatzi A, Manganas P, Tokatlidis K. Oxidative folding in the mitochondrial intermembrane space: a regulated process important for cell physiology and disease. Biochim Biophys Acta. 2016;1863(6PtA):1298–306.CrossRefPubMedGoogle Scholar
  4. 4.
    Chaban Y, Boekema EJ, Dudkina NV. Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilization. Biochim Biophys Acta. 2014;1837(4):418–26.CrossRefPubMedGoogle Scholar
  5. 5.
    Schägger H, Pfeiffer K. Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J. 2000;19(8):1777–83.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84(1):277–359.CrossRefPubMedGoogle Scholar
  7. 7.
    • Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science (New York, NY). 2012;337:1062–5. Description and relevance of mitochondrial fussion and fission processes. Google Scholar
  8. 8.
    Malka F, Guillery O, Cifuentes-Diaz C, Guillou E, Belenguer P, Lombes A, et al. Separate fusion of outer and inner mitochondrial membranes. EMBO Rep. 2005;6:853–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    •• Quiros PM, Ramsay AJ, Sala D, Fernandez-Vizarra E, Rodriguez F, Peinado JR, et al. Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J. 2012;31:2117–33. This study provides the first description of OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function. Google Scholar
  10. 10.
    Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol. 2009;187:959–66.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.•
    Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007;178(5):749–55. The study shows that mammalian cells have multiple pathways to control mitochondrial fusion through regulation of the spectrum of OPA1 isoforms. Google Scholar
  12. 12.
    • Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001;12(8):2245–56. The study shows that Drp1 contributes to mitochondrial division in mammalian cells. Google Scholar
  13. 13.
    van der Bliek AM, Shen Q, Kawajiri S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol. 2013;5:a011072.PubMedPubMedCentralGoogle Scholar
  14. 14.
    • Ploumi C, Daskalaki I, Tavernarakis N. Mitochondrial biogenesis and clearance: a balancing act. FEBS J. 2016; Jul 27. doi:  10.1111/febs.13820. A review of recent findings that highlight the importance of the mitochondrial biogenesis and underlying molecular mechanisms in energy production and the cellular processes.
  15. 15.
    Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, et al. PINK1-dependent recruitment of PARKIN to mitochondria in mitophagy. Proc Natl Acad Sci U S A. 2010;107(1):378–83. doi: 10.1073/pnas.0911187107.CrossRefPubMedGoogle Scholar
  16. 16.
    Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, et al. Mitochondrial bioenergetics and structural network organization. J Cell Sci. 2007;120:838–48.CrossRefPubMedGoogle Scholar
  17. 17.
    • Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17:491–506. The study describe that mitochondrial dynamics provide a new mechanism linking excess nutrient environment to progressive mitochondrial dysfunction, common to age-related diseases. Google Scholar
  18. 18.
    Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 2009;28:1589–600.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    • Bournat JC, Brown CW. Mitochondrial dysfunction in obesity. Curr Opin Endocrinol Diabetes Obes. 2010;17(5):446–52. The review highlights recent findings regarding the functions of mitochondria in adipocytes, in regulating substrate metabolism, energy expenditure, disposal of reactive oxygen species (ROS), and in the pathophysiology of obesity and insulin resistance. Google Scholar
  20. 20.
    •• Dietrich MO, Liu ZW, Horvath TL. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell. 2013;155:188–99. The study shows the important role for mitochondrial dynamics governed by Mfn1 and Mfn2 in Agrp neurons in central regulation of whole-body energy metabolism. Google Scholar
  21. 21.
    •• Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab. 2016;27(2):105–17. The review describe the ways in which metabolic alterations convey changes in mitochondrial morphology and how disruption of mitochondrial morphology impacts cellular and organismal metabolism. Google Scholar
  22. 22.
    •• Manucha W, Ritchie B, Ferder L. Hypertension and insulin resistance: implications of mitochondrial dysfunction. Curr Hypertens Rep. 2015;17(1):504. The review describes that mitochondria possess both a functional RAS and vitamin D receptors and its relevance in hypertension and diabetes. Google Scholar
  23. 23.
    Baltrusch S. Mitochondrial network regulation and its potential interference with inflammatory signals in pancreatic beta cells. Diabetologia. 2016;59(4):683–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang Z, Wakabayashi N, Wakabayashi J, Tamura Y, Song WJ, Sereda S, et al. The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol Biol Cell. 2011;22:2235–45.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, et al. Critical reappraisal confirms that mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci U S A. 2016;113(40):11249–54.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    •• Friedman JR, Nunnari J. Mitochondrial form and function. Nature. 2014;505:335–43. The study pictures mitochondria as ‘super-organized’ organelle responsible for regulation of cellular needs, as well as its own dysfunction. Google Scholar
  27. 27.
    Bansal S, Biswas G, Avadhani NG. Mitochondria-targeted heme oxygenase-1 induces oxidative stress and mitochondrial dysfunction in macrophages, kidney fibroblasts and in chronic alcohol hepatotoxicity. Redox Biol. 2013;2:273–83.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Camporez JP, Asrih M, Zhang D, Kahn M, Samuel VT, Jurczak MJ, et al. Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21. J Endocrinol. 2015;226:207–17.CrossRefPubMedGoogle Scholar
  29. 29.
    Sebastián D, Hernández-Alvarez MI, Segalés J, Sorianello E, Muñoz JP, Sala D, et al. Mitofusin 2 (Mfn2) links mitocondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci U S A. 2012;109:5523–8.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Touvier T, De Palma C, Rigamonti E, Scagliola A, Incerti E, Mazelin L, et al. Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation. Cell Death Dis. 2015;6:e1663.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol. 2015;11:11–24.CrossRefPubMedGoogle Scholar
  32. 32.
    •• Schneeberger M, Dietrich MO, Sebastián D, Imbernón M, Castaño C, Garcia A, et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell. 2013;155:172–87. The results establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. Google Scholar
  33. 33.
    • Zorzano A, Claret M. Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction. Front Aging Neurosci. 2015;7:101. The review shows findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction. Google Scholar
  34. 34.
    Barki-Harrington L, Perrino C, Rockman HA. Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc Res. 2004;63:391–402.CrossRefPubMedGoogle Scholar
  35. 35.
    Taigen T, De Windt LJ, Lim HW, Molkentin JD. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2000;97:1196–201.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356:1140–51.CrossRefPubMedGoogle Scholar
  37. 37.•
    Zamorano-León JJ, Modrego J, Mateos-Cáceres PJ, Macaya C, Martín-Fernández B, Miana M, et al. A proteomic approach to determine changes in proteins involved in the myocardial metabolism in left ventricles of spontaneously hypertensive rats. Cell Physiol Biochem. 2010;25:347–58. The study is a proteomic approach showing changes in proteins involved in the metabolism of left ventricles of hypertensive rats. Google Scholar
  38. 38.
    Shen W, Asai K, Uechi M, Mathier MA, Shannon RP, Vatner SF, et al. Progressive loss of myocardial ATP due to a loss of total purines during the development of the heart failure in dogs. Circulation. 1999;100:2113–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation. 2010;121:2012–22.CrossRefPubMedGoogle Scholar
  40. 40.
    Fang L, Moore XL, Gao XM, Dart AM, Lim YL, Du XJ. Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci. 2007;80:2154–60.CrossRefPubMedGoogle Scholar
  41. 41.
    •• Pennanen C, Parra V, López-Crisosto C, Morales PE, del Campo A, Gutierrez T, et al. Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. J Cell Sci. 2014;127:2659–71. The results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling. Google Scholar
  42. 42.
    Santel A, Frank S. Shaping mitochondria: the complex posttranslational regulation of the mitochondrial fission protein DRP1. IUBMB Life. 2008;60:448–55.CrossRefPubMedGoogle Scholar
  43. 43.
    Ashrafian H, Docherty L, Leo V, Towlson C, Neilan M, Steeples V, et al. A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy. Plos Genet. 2010;6(6):e1001000.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    • López Farré A, Casado S. Heart failure, redox alterations, and endothelial dysfunction. Hypertension. 2001;38:1400–5. The review analyzes the involvement of ROS in the cellular and molecular mechanisms associated with endothelial dysfunction in heart failure. Google Scholar
  45. 45.
    van Empel VP, De Windt LJ. Myocyte hypertrophy and apoptosis: a balancing act. Cardiovasc Res. 2004;63(3):487–99.CrossRefPubMedGoogle Scholar
  46. 46.
    Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Front Oncol. 2013;3:292.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mazzei L, García M, Calvo JP, Casarotto M, Fornés M, Abud MA, et al. Changes in renal WT-1 expression preceding hypertension development. BMC Nephrol. 2016;17:34.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Mazzei L, Docherty NG, Manucha W. Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy. Cell Stress Chaperones. 2015;20:893–906.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhang X, Li ZL, Crane JA, Jordan KL, Pawar AS, Textor SC, et al. Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension. Hypertension. 2014;64(1):87–93.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    • Liu C, Yang Q, Hwang SJ, Sun F, Johnson AD, Shirihai OS, et al. Association of genetic variation in the mitochondrial genome with blood pressure and metabolic traits. Hypertension. 2012;60:949–56. The study provide the first evidence of association of variants in the mitochondrial genome with systolic blood pressure and fasting blood glucose in general population. Google Scholar
  51. 51.
    Jian MY, Alexeyev MF, Wolkowicz PE, Zmijewski JW, Creighton JR. Metformin stimulated AMPKα1 promotes microvascular repair in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2013;305:L844–55.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wang S, Li R, Fettermann A, Li Z, Qian Y, Liu Y, et al. Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mitochondrial tRNAlle gene in a large Han Chinese family. Circ Res. 2011;108(7):862–70.CrossRefPubMedGoogle Scholar
  53. 53.
    Andersen G, Wegner L, Jensen DP, Glümer C, Tarnow L, Drivsholm T, et al. PGC-1alpha Gly482Ser polymorphism associates with hypertension among Danish whites. Hypertension. 2005;45(4):565–70.CrossRefPubMedGoogle Scholar
  54. 54.
    Bengtsson B, Thulin T, Schersten B. Familial resemblance in casual blood pressure—a maternal effect? Clin Sci (Lond). 1979;57 Suppl 5:279s–81s.CrossRefGoogle Scholar
  55. 55.
    Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J, et al. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest. 2004;114(9):1281–9.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Blanquer-Rosselló MM, Santandreu FM, Oliver J, Roca P, Valle A. Leptin modulates mitochondrial function, dynamics and biogenesis in MCF-7 cells. J Cell Biochem. 2015;116(9):2039–48.CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang W, Ambati S, Della-Fera MA, Choi YH, Baile CA, Andacht TM. Leptin modulated changes in adipose tissue protein expression in ob/ob mice. Obesity (Silver Spring). 2011;19(2):255–61.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Vicente Lahera
    • 1
    Email author
  • Natalia de las Heras
    • 1
  • Antonio López-Farré
    • 2
  • Walter Manucha
    • 3
    • 4
  • León Ferder
    • 5
  1. 1.Department of Physiology, School of MedicineComplutense UniversityMadridSpain
  2. 2.Department of Medicine, School of MedicineComplutense UniversityMadridSpain
  3. 3.Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)MendozaArgentina
  4. 4.Área de Farmacología, Departamento de Patología, Facultad de Ciencias MédicasUniversidad Nacional de CuyoMendozaArgentina
  5. 5.Pediatric Department Nephrology Division, Miller School of MedicineUniversity of MiamiMiamiUSA

Personalised recommendations