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Mitochondrial membrane transporters and metabolic switch in heart failure

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Abstract

Mitochondrial dysfunction is widely recognized as a major factor for the progression of cardiac failure. Mitochondrial uptake of metabolic substrates and their utilization for ATP synthesis, electron transport chain activity, reactive oxygen species levels, ion homeostasis, mitochondrial biogenesis, and dynamics as well as levels of reactive oxygen species in the mitochondria are key factors which regulate mitochondrial function in the normal heart. Alterations in these functions contribute to adverse outcomes in heart failure. Iron imbalance and oxidative stress are also major factors for the evolution of cardiac hypertrophy, heart failure, and aging-associated pathological changes in the heart. Mitochondrial ATP–binding cassette (ABC) transporters have a key role in regulating iron metabolism and maintenance of redox status in cells. Deficiency of mitochondrial ABC transporters is associated with an impaired mitochondrial electron transport chain complex activity, iron overload, and increased levels of reactive oxygen species, all of which can result in mitochondrial dysfunction. In this review, we discuss the role of mitochondrial ABC transporters in mitochondrial metabolism and metabolic switch, alterations in the functioning of ABC transporters in heart failure, and mitochondrial ABC transporters as possible targets for therapeutic intervention in cardiac failure.

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References

  1. Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JGF, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ, Gheorghiade M (2017) Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol 14(4):238–250. https://doi.org/10.1038/nrcardio.2016.203

    Article  CAS  PubMed  Google Scholar 

  2. O’Rourke B (2016) Metabolism: beyond the power of mitochondria. Nat Rev Cardiol 13:386–387. https://doi.org/10.1038/nrcardio.2016.95

    Article  CAS  PubMed  Google Scholar 

  3. Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129. https://doi.org/10.1152/physrev.00006.2004

    Article  CAS  PubMed  Google Scholar 

  4. Barry WH (2004) Heart physiology from cell to circulation, 4th ed. Circulation 110:e313–e313. https://doi.org/10.1161/01.CIR.0000143724.99618.62

    Article  Google Scholar 

  5. Andersson B, Blomström-Lundqvist C, Hedner T, Waagstein F (1991) Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure. J Am Coll Cardiol 18(4):1059–1066. https://doi.org/10.1016/0735-1097(91)90767-4

    Article  CAS  PubMed  Google Scholar 

  6. Agnetti G, Kaludercic N, Kane LA, Elliott ST, Guo Y, Chakir K, Samantapudi D, Paolocci N, Tomaselli GF, Kass DA, van Eyk JE (2010) Modulation of mitochondrial proteome and improved mitochondrial function by biventricular pacing of dyssynchronous failing hearts. Circ Cardiovasc Genet 3:78–87. https://doi.org/10.1161/CIRCGENETICS.109.871236

    Article  CAS  PubMed  Google Scholar 

  7. Palmer JW, Tandler B, Hoppel CL (1985) Biochemical differences between subsarcolemmal and interfibrillar mitochondria from rat cardiac muscle: effects of procedural manipulations. Arch Biochem Biophys 236:691–702. https://doi.org/10.1016/0003-9861(85)90675-7

    Article  CAS  PubMed  Google Scholar 

  8. Lukyanenko V, Chikando A, Lederer WJ (2009) Mitochondria in cardiomyocyte Ca2+ signaling. Int J Biochem Cell Biol 41:1957–1971. https://doi.org/10.1016/j.biocel.2009.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Riva A, Tandler B, Loffredo F, Vazquez E, Hoppel C (2005) Structural differences in two biochemically defined populations of cardiac mitochondria. Am J Physiol Circ Physiol 289:H868–H872. https://doi.org/10.1152/ajpheart.00866.2004

    Article  CAS  Google Scholar 

  10. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839. https://doi.org/10.1016/S0092-8674(00)81410-5

    Article  CAS  PubMed  Google Scholar 

  11. Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368. https://doi.org/10.1101/gad.1177604.GENES

    Article  CAS  PubMed  Google Scholar 

  12. Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 79:208–217. https://doi.org/10.1093/cvr/cvn098

    Article  CAS  PubMed  Google Scholar 

  13. Dufour CR, Wilson BJ, Huss JM, Kelly DP, Alaynick WA, Downes M, Evans RM, Blanchette M, Giguère V (2007) Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ. Cell Metab 5:345–356. https://doi.org/10.1016/j.cmet.2007.03.007

    Article  CAS  PubMed  Google Scholar 

  14. Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, Medeiros DM, Valencik ML, McDonald JA, Kelly DP (2004) Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res 94:525–533. https://doi.org/10.1161/01.RES.0000117088.36577.EB

    Article  CAS  PubMed  Google Scholar 

  15. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856. https://doi.org/10.1172/JCI10268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stojanovski D, Guiard B, Kozjak-Pavlovic V, Pfanner N, Meisinger C (2007) Alternative function for the mitochondrial SAM complex in biogenesis of α-helical TOM proteins. J Cell Biol 179:881–893. https://doi.org/10.1083/jcb.200706043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wiedemann N, Pfanner N (2017) Mitochondrial machineries for protein import and assembly. Annu Rev Biochem 86:685–714. https://doi.org/10.1146/annurev-biochem-060815-014352

    Article  CAS  PubMed  Google Scholar 

  18. Hulbert AJ, Turner N, Hinde J, Else P, Guderley H (2006) How might you compare mitochondria from different tissues and different species? J Comp Physiol B Biochem Syst Environ Physiol 176:93–105. https://doi.org/10.1007/s00360-005-0025-z

    Article  CAS  Google Scholar 

  19. Herbers E, Kekäläinen NJ, Hangas A et al (2018) Tissue specific differences in mitochondrial DNA maintenance and expression. Mitochondrion S1567-7249(17):30342–30342. https://doi.org/10.1016/j.mito.2018.01.004

    Article  CAS  Google Scholar 

  20. Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S (1992) Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol 24:1333–1347. https://doi.org/10.1016/0022-2828(92)93098-5

    Article  CAS  PubMed  Google Scholar 

  21. Sabbah HN (2016) Targeting mitochondrial dysfunction in the treatment of heart failure. Expert Rev Cardiovasc Ther 14:1305–1313. https://doi.org/10.1080/14779072.2016.1249466

    Article  CAS  PubMed  Google Scholar 

  22. Bacman SR, Williams SL, Pinto M, Peralta S, Moraes CT (2013) Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat Med 19:1111–1113. https://doi.org/10.1038/nm.3261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu F, Zhang J, Beard DA (2009) Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism. Proc Natl Acad Sci U S A 106:7143–7148. https://doi.org/10.1073/pnas.0812768106

    Article  PubMed  PubMed Central  Google Scholar 

  24. Aubert G, Vega RB, Kelly DP (2013) Perturbations in the gene regulatory pathways controlling mitochondrial energy production in the failing heart. Biochim Biophys Acta 1833:840–847. https://doi.org/10.1016/j.bbamcr.2012.08.015

    Article  CAS  PubMed  Google Scholar 

  25. Ventura-Clapier R, Garnier A, Veksler V (2004) Energy metabolism in heart failure. J Physiol 555:1–13. https://doi.org/10.1113/jphysiol.2003.055095

    Article  CAS  PubMed  Google Scholar 

  26. Sarma S, Ardehali H, Gheorghiade M (2012) Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure. Heart Fail Rev 17:35–43. https://doi.org/10.1007/s10741-010-9208-0

    Article  CAS  PubMed  Google Scholar 

  27. Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD (2011) Targeting fatty acid and carbohydrate oxidation — a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta 1813:1333–1350. https://doi.org/10.1016/j.bbamcr.2011.01.015

    Article  CAS  PubMed  Google Scholar 

  28. Lodish H, Berk A, Zipursky SL et al (2000) Molecular cell biology, 4th edn. York, New

    Google Scholar 

  29. Chappell JB (1968) Systems used for the transport of substrates into mitochondria. Br Med Bull 24:150–157. https://doi.org/10.1093/oxfordjournals.bmb.a070618

    Article  CAS  PubMed  Google Scholar 

  30. Wohlrab H, Greaney J (1978) Mitochondrial phosphate transport and the N-ethylmaleimide binding proteins of the inner membrane. BBA-Bioenergetics 503:425–436. https://doi.org/10.1016/0005-2728(78)90142-1

    Article  CAS  PubMed  Google Scholar 

  31. Kaplan RS, Pedersen PL (1983) Characterization of phosphate efflux pathways in rat liver mitochondria. Biochem J 212:279–288. https://doi.org/10.1042/bj2120279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gnoni GV, Priore P, Geelen MJH, Siculella L (2009) The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. IUBMB Life 61:987–994. https://doi.org/10.1002/iub.249

    Article  CAS  PubMed  Google Scholar 

  33. Hayes DJ, Taylor DJ, Bore PJ, Hilton-Jones D, Arnold DL, Squier MV, Gent AE, Radda GK (1987) An unusual metabolic myopathy: a malate-aspartate shuttle defect. J Neurol Sci 82:27–39. https://doi.org/10.1016/0022-510X(87)90004-9

    Article  CAS  PubMed  Google Scholar 

  34. Atlante A, Passarella S, Giannattasio S, Quagliariello E (1985) Fumarate permeation in rat liver mitochondria: fumarate/malate and fumarate/phosphate translocators. Biochem Biophys Res Commun 132:8–18. https://doi.org/10.1016/0006-291X(85)90981-7

    Article  CAS  PubMed  Google Scholar 

  35. De Bari L, Atlante A, Guaragnella N et al (2002) D-Lactate transport and metabolism in rat liver mitochondria. Biochem J 365:391–403. https://doi.org/10.1042/BJ20020139

    Article  PubMed  PubMed Central  Google Scholar 

  36. Esparza A, Gerdtzen ZP, Olivera-Nappa A, Salgado JC, Núñez MT (2015) Iron-induced reactive oxygen species mediate transporter DMT1 endocytosis and iron uptake in intestinal epithelial cells. Am J Phys Cell Phys 309:C558–C567. https://doi.org/10.1152/ajpcell.00412.2014

    Article  CAS  Google Scholar 

  37. Mouli S, Nanayakkara G, AlAlasmari A, Eldoumani H, Fu X, Berlin A, Lohani M, Nie B, Arnold RD, Kavazis A, Smith F, Beyers R, Denney T, Dhanasekaran M, Zhong J, Quindry J, Amin R (2015) The role of frataxin in doxorubicin mediated cardiac hypertrophy. Am J Physiol Heart Circ Physiol 309:H844–H859. https://doi.org/10.1152/ajpheart.00182.2015

    Article  CAS  PubMed  Google Scholar 

  38. Lakhal-Littleton S, Wolna M, Carr CA, Miller JJJ, Christian HC, Ball V, Santos A, Diaz R, Biggs D, Stillion R, Holdship P, Larner F, Tyler DJ, Clarke K, Davies B, Robbins PA (2015) Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. Proc Natl Acad Sci 112:3164–3169. https://doi.org/10.1073/pnas.1422373112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sarkadi B, Homolya L, Szakács G, Váradi A (2006) Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev 86:1179–1236. https://doi.org/10.1152/physrev.00037.2005

    Article  CAS  PubMed  Google Scholar 

  40. Solbach TF, König J, Fromm MF, Zolk O (2006) ATP-binding cassette transporters in the heart. Trends Cardiovasc Med 16:7–15. https://doi.org/10.1016/j.tcm.2005.10.001

    Article  CAS  PubMed  Google Scholar 

  41. Zutz A, Gompf S, Schägger H, Tampé R (2009) Mitochondrial ABC proteins in health and disease. Biochim Biophys Acta Bioenerg 1787:681–690. https://doi.org/10.1016/j.bbabio.2009.02.009

    Article  CAS  Google Scholar 

  42. Schaedler TA, Faust B, Shintre CA et al (2015) Structures and functions of mitochondrial ABC transporters. Biochem Soc Trans 43:943–951. https://doi.org/10.1042/BST20150118

    Article  CAS  PubMed  Google Scholar 

  43. Zhabyeyev P, Oudit GY (2017) Unravelling the molecular basis for cardiac iron metabolism and deficiency in heart failure. Eur Heart J 38:373–375. https://doi.org/10.1093/eurheartj/ehw386

    Article  PubMed  Google Scholar 

  44. Seguin A, Ward DM (2018) Mitochondrial ABC transporters and iron metabolism. J Clin Exp Pathol 8:338. https://doi.org/10.4172/2161-0681.1000338

    Article  Google Scholar 

  45. Zhabyeyev P, Oudit GY (2016) Unravelling the molecular basis for cardiac iron metabolism and deficiency in heart failure. Eur Heart J 38:373–375. https://doi.org/10.1093/eurheartj/ehw386

    Article  PubMed Central  Google Scholar 

  46. Haddad S, Wang Y, Galy B, Korf-Klingebiel M, Hirsch V, Baru AM, Rostami F, Reboll MR, Heineke J, Flögel U, Groos S, Renner A, Toischer K, Zimmermann F, Engeli S, Jordan J, Bauersachs J, Hentze MW, Wollert KC, Kempf T (2016) Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J 38:362–372. https://doi.org/10.1093/eurheartj/ehw333

    Article  CAS  Google Scholar 

  47. Kiss K, Kucsma N, Brozik A, Tusnady GE, Bergam P, van Niel G, Szakacs G (2015) Role of the N-terminal transmembrane domain in the endo-lysosomal targeting and function of the human ABCB6 protein. Biochem J 467:127–139. https://doi.org/10.1042/BJ20141085

    Article  CAS  PubMed  Google Scholar 

  48. Helias V, Saison C, Ballif BA, Peyrard T, Takahashi J, Takahashi H, Tanaka M, Deybach JC, Puy H, le Gall M, Sureau C, Pham BN, le Pennec PY, Tani Y, Cartron JP, Arnaud L (2012) ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet 44:170–173. https://doi.org/10.1038/ng.1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Paterson JK, Shukla S, Black CM, Tachiwada T, Garfield S, Wincovitch S, Ernst DN, Agadir A, Li X, Ambudkar SV, Szakacs G, Akiyama SI, Gottesman MM (2007) Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry 46:9443–9452. https://doi.org/10.1021/bi700015m

    Article  CAS  PubMed  Google Scholar 

  50. Krishnamurthy PC, Du G, Fukuda Y et al (2006) Identification of a mammalian mitochondrial porphyrin transporter. Nature 443:586–589. https://doi.org/10.1038/nature05125

    Article  CAS  PubMed  Google Scholar 

  51. Mitsuhashi N, Miki T, Senbongi H, Yokoi N, Yano H, Miyazaki M, Nakajima N, Iwanaga T, Yokoyama Y, Shibata T, Seino S (2000) MTABC3, a novel mitochondrial ATP-binding cassette protein involved in iron homeostasis. J Biol Chem 275:17536–17540. https://doi.org/10.1074/jbc.275.23.17536

    Article  CAS  PubMed  Google Scholar 

  52. Matsumoto K, Hagiya Y, Endo Y, Nakajima M, Ishizuka M, Tanaka T, Ogura SI (2015) Effects of plasma membrane ABCB6 on 5-aminolevulinic acid (ALA)-induced porphyrin accumulation in vitro: tumor cell response to hypoxia. Photodiagn Photodyn Ther 12:45–51. https://doi.org/10.1016/j.pdpdt.2014.12.008

    Article  CAS  Google Scholar 

  53. Fukuda Y, Cheong PL, Lynch J, Brighton C, Frase S, Kargas V, Rampersaud E, Wang Y, Sankaran VG, Yu B, Ney PA, Weiss MJ, Vogel P, Bond PJ, Ford RC, Trent RJ, Schuetz JD (2016) The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6. Nat Commun 7:12353. https://doi.org/10.1038/ncomms12353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Paul VD, Lill R (2015) Biogenesis of cytosolic and nuclear iron–sulfur proteins and their role in genome stability. Biochim Biophys Acta Mol Cell Res 1853:1528–1539. https://doi.org/10.1016/j.bbamcr.2014.12.018

    Article  CAS  Google Scholar 

  55. Li J, Cowan JA (2015) Glutathione-coordinated [2Fe–2S] cluster: a viable physiological substrate for mitochondrial ABCB7 transport. Chem Commun 51:2253–2255. https://doi.org/10.1039/C4CC09175B

    Article  CAS  Google Scholar 

  56. Schaedler TA, Thornton JD, Kruse I, Schwarzländer M, Meyer AJ, van Veen HW, Balk J (2014) A conserved mitochondrial ATP-binding cassette transporter exports glutathione polysulfide for cytosolic metal cofactor assembly. J Biol Chem 289:23264–23274. https://doi.org/10.1074/jbc.M114.553438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Taketani S, Kakimoto K, Ueta H et al (2003) Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase. Blood 101:3274–3280. https://doi.org/10.1182/blood-2002-04-1212

    Article  CAS  PubMed  Google Scholar 

  58. Csere P, Lill R, Kispal G (1998) Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p. FEBS Lett 441:266–270. https://doi.org/10.1016/S0014-5793(98)01560-9

    Article  CAS  PubMed  Google Scholar 

  59. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM (1999) Mutation of a putative mitochondrial Iron transporter gene (ABC7) in X-Linked Sideroblastic Anemia and Ataxia (XLSA/a). Hum Mol Genet 8:743–749. https://doi.org/10.1093/hmg/8.5.743

    Article  CAS  PubMed  Google Scholar 

  60. Kispal G, Csere P, Prohl C, Lill R (1999) The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J 18:3981–3989. https://doi.org/10.1093/emboj/18.14.3981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pondarré C, Antiochos BB, Campagna DR, Clarke SL, Greer EL, Deck KM, McDonald A, Han AP, Medlock A, Kutok JL, Anderson SA, Eisenstein RS, Fleming MD (2006) The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron–sulfur cluster biogenesis. Hum Mol Genet 15:953–964. https://doi.org/10.1093/hmg/ddl012

    Article  CAS  PubMed  Google Scholar 

  62. Ichikawa Y, Bayeva M, Ghanefar M, Potini V, Sun L, Mutharasan RK, Wu R, Khechaduri A, Jairaj Naik T, Ardehali H (2012) Disruption of ATP-binding cassette B8 in mice leads to cardiomyopathy through a decrease in mitochondrial iron export. Proc Natl Acad Sci 109:4152–4157. https://doi.org/10.1073/pnas.1119338109

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Prasad SVN, Mutharasan RK, Naik TJ, Ardehali H (2014) Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124:617–630. https://doi.org/10.1172/JCI72931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hyde BB, Liesa M, Elorza AA, Qiu W, Haigh SE, Richey L, Mikkola HK, Schlaeger TM, Shirihai OS (2012) The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo. Cell Death Differ 19:1117–1126. https://doi.org/10.1038/cdd.2011.195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Liesa M, Luptak I, Qin F, Hyde BB, Sahin E, Siwik DA, Zhu Z, Pimentel DR, Xu XJ, Ruderman NB, Huffman KD, Doctrow SR, Richey L, Colucci WS, Shirihai OS (2011) Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion. Circulation 124(68):806–813. https://doi.org/10.1161/CIRCULATIONAHA.110.003418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen W, Dailey HA, Paw BH (2010) Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood 116:628–630. https://doi.org/10.1182/blood-2009-12-259614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen W, Paradkar PN, Li L, Pierce EL, Langer NB, Takahashi-Makise N, Hyde BB, Shirihai OS, Ward DM, Kaplan J, Paw BH (2009) Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. Proc Natl Acad Sci 106:16263–16268. https://doi.org/10.1073/pnas.0904519106

    Article  PubMed  PubMed Central  Google Scholar 

  68. Liesa M, Qiu W, Shirihai OS (2012) Mitochondrial ABC transporters function: the role of ABCB10 (ABC-me) as a novel player in cellular handling of reactive oxygen species. Biochim Biophys Acta Mol Cell Res 1823(10):1945–1957. https://doi.org/10.1016/j.bbamcr.2012.07.013

    Article  CAS  Google Scholar 

  69. Couture L (2006) The ATP-binding cassette transporters and their implication in drug disposition: a special look at the heart. Pharmacol Rev 58:244–258. https://doi.org/10.1124/pr.58.2.7

    Article  CAS  PubMed  Google Scholar 

  70. J. Patterson A, Zhang L (2010) Hypoxia and fetal heart development. Curr Mol Med 10:653–666. https://doi.org/10.2174/156652410792630643

    Article  Google Scholar 

  71. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, Santos CX, Thet SW, Mori E, Kinter MT, Rindler PM, Zacchigna S, Mukherjee S, Chen DJ, Mahmoud AI, Giacca M, Rabinovitch PS, Asaithamby A, Shah AM, Szweda LI, Sadek HA (2014) The oxygen rich postnatal environment induces cardiomyocyte cell cycle arrest through DNA damage response. Cell 157:565–579. https://doi.org/10.1016/j.cell.2014.03.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gibbs CL (1978) Cardiac energetics. Physiol Rev 58:174–254. https://doi.org/10.1152/physrev.1978.58.1.174

    Article  CAS  PubMed  Google Scholar 

  73. Kolwicz SC, Purohit S, Tian R (2013) Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res 113:603–616. https://doi.org/10.1161/CIRCRESAHA.113.302095

    Article  CAS  PubMed  Google Scholar 

  74. Schaper J, Meiser E, Stammler G (1985) Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts. Circ Res 56:377–391. https://doi.org/10.1161/01.RES.56.3.377

    Article  CAS  PubMed  Google Scholar 

  75. Beer M, Seyfarth T, Sandstede J, Landschütz W, Lipke C, Köstler H, von Kienlin M, Harre K, Hahn D, Neubauer S (2002) Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with 31P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol 40:1267–1274. https://doi.org/10.1016/S0735-1097(02)02160-5

    Article  CAS  PubMed  Google Scholar 

  76. Doenst T, Nguyen TD, Abel ED (2013) Cardiac metabolism in heart failure. Circ Res 113:709–724. https://doi.org/10.1161/CIRCRESAHA.113.300376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D’Onofrio F (1994) Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 43:174–179. https://doi.org/10.1016/0026-0495(94)90241-0

    Article  CAS  PubMed  Google Scholar 

  78. Rimbaud S, Sanchez H, Garnier A, Fortin D, Bigard X, Veksler V, Ventura-Clapier R (2009) Stimulus specific changes of energy metabolism in hypertrophied heart. J Mol Cell Cardiol 46:952–959. https://doi.org/10.1016/j.yjmcc.2009.01.013

    Article  CAS  PubMed  Google Scholar 

  79. Camici P, Marraccini P, Marzilli M, Lorenzoni R, Buzzigoli G, Puntoni R, Boni C, Bellina CR, Klassen GA, L'Abbate A et al (1989) Coronary hemodynamics and myocardial metabolism during and after pacing stress in normal humans. Am J Phys 257:E309–E317. https://doi.org/10.1152/ajpendo.1989.257.3.E309

    Article  CAS  Google Scholar 

  80. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ (2002) Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 40:271–277. https://doi.org/10.1016/S0735-1097(02)01967-8

    Article  PubMed  Google Scholar 

  81. Wallhaus TR, Taylor M, DeGrado TR et al (2001) Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 103:2441–2446. https://doi.org/10.1161/01.CIR.103.20.2441

    Article  CAS  PubMed  Google Scholar 

  82. Pellieux C, Aasum E, Larsen TS, Montessuit C, Papageorgiou I, Pedrazzini T, Lerch R (2006) Overexpression of angiotensinogen in the myocardium induces downregulation of the fatty acid oxidation pathway. J Mol Cell Cardiol 41:459–466. https://doi.org/10.1016/j.yjmcc.2006.06.004

    Article  CAS  PubMed  Google Scholar 

  83. Pellieux C, Montessuit C, Papageorgiou I, Lerch R (2009) Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-α. Cardiovasc Res 82:341–350. https://doi.org/10.1093/cvr/cvp004

    Article  CAS  PubMed  Google Scholar 

  84. Nascimben L, Ingwall JS, Pauletto P, Friedrich J, Gwathmey JK, Saks V, Pessina AC, Allen PD (1996) Creatine kinase system in failing and nonfailing human myocardium. Circulation 94:1894–1901. https://doi.org/10.1161/01.CIR.94.8.1894

    Article  CAS  PubMed  Google Scholar 

  85. Hardy CJ, Weiss RG, Bottomley PA, Gerstenblith G (1991) Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy. Am Heart J 122:795–801. https://doi.org/10.1016/0002-8703(91)90527-O

    Article  CAS  PubMed  Google Scholar 

  86. Wittels B, Spann JF (1968) Defective lipid metabolism in the failing heart. J Clin Invest 47:1787–1794. https://doi.org/10.1172/JCI105868

    Article  CAS  PubMed  Google Scholar 

  87. Panchal AR, Stanley WC, Kerner J, Sabbah HN (1998) Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure. J Card Fail 4:121–126. https://doi.org/10.1016/S1071-9164(98)90252-4

    Article  CAS  PubMed  Google Scholar 

  88. Rouslin W, Broge CW (1993) Mechanisms of ATP conservation during ischemia in slow and fast heart rate hearts. Am J Physiol 264:C209–C216. https://doi.org/10.1152/ajpcell.1993.264.1.C209

    Article  CAS  PubMed  Google Scholar 

  89. Cannon MV, Sillje HH, Sijbesma JW, Vreeswijk-Baudoin I, Ciapaite J, van der Sluis B, van Deursen J, Silva GJ, de Windt LJ, Gustafsson JA, van der Harst P, van Gilst WH, de Boer RA (2015) Cardiac LXR protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization. EMBO Mol Med 7:1229–1243. https://doi.org/10.15252/emmm.201404669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. O’Donnell JM, White LT, Lewandowski ED (1999) Mitochondrial transporter responsiveness and metabolic flux homeostasis in postischemic hearts. Am J Phys 277:H866–H873. https://doi.org/10.1152/ajpheart.1999.277.3.H866

    Article  Google Scholar 

  91. Walther T, Tschöpe C, Sterner-Kock A et al (2007) Accelerated mitochondrial adenosine diphosphate/adenosine triphosphate transport improves hypertension-induced heart disease. Circulation 115:333–344. https://doi.org/10.1161/CIRCULATIONAHA.106.643296

    Article  CAS  PubMed  Google Scholar 

  92. Sigauke E, Rakheja D, Kitson K, Bennett MJ (2003) Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review. Lab Investig 83:1543–1554. https://doi.org/10.1097/01.LAB.0000098428.51765.83

    Article  CAS  PubMed  Google Scholar 

  93. Djouadi F, Bonnefont J-P, Thuillier L, Droin V, Khadom N, Munnich A, Bastin J (2003) Correction of fatty acid oxidation in carnitine palmitoyl transferase 2–deficient cultured skin fibroblasts by bezafibrate. Pediatr Res 54:446–451. https://doi.org/10.1203/01.PDR.0000083001.91588.BB

    Article  CAS  PubMed  Google Scholar 

  94. Gibb AA, Epstein PN, Uchida S, Zheng Y, McNally LA, Obal D et al (2017) Exercise-induced changes in glucose metabolism promote physiologic cardiac growth. Circulation 136:2144–2157. https://doi.org/10.1161/CIRCULATIONAHA.117.028274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rines AK, Ardehali H (2013) Transition metals and mitochondrial metabolism in the heart. J Mol Cell Cardiol 55:50–57. https://doi.org/10.1016/j.yjmcc.2012.05.014

    Article  CAS  PubMed  Google Scholar 

  96. Andrews NC (1999) Disorders of iron metabolism. N Engl J Med 341:1986–1995. https://doi.org/10.1056/NEJM199912233412607

    Article  CAS  PubMed  Google Scholar 

  97. Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P (2013) Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J 34:816–829. https://doi.org/10.1093/eurheartj/ehs224

    Article  CAS  PubMed  Google Scholar 

  98. Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, von Haehling S, Macdougall IC, Weiss G, McMurray JJV, Anker SD, Gheorghiade M, Ponikowski P (2013) Iron status in patients with chronic heart failure. Eur Heart J 34:827–834. https://doi.org/10.1093/eurheartj/ehs377

    Article  CAS  PubMed  Google Scholar 

  99. Sukumaran A, Chang J, Han M, Mintri S, Khaw BA, Kim J (2017) Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis. Sci Rep 7(5756):5756. https://doi.org/10.1038/s41598-017-05810-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Das SK, Wang W, Zhabyeyev P, Basu R, McLean B, Fan D, Parajuli N, DesAulniers J, Patel VB, Hajjar RJ, Dyck JRB, Kassiri Z, Oudit GY (2016) Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. Sci Rep 5:18132. https://doi.org/10.1038/srep18132

    Article  CAS  Google Scholar 

  101. Medeiros DM, Jiang Y, Klaahsen D, Lin D (2009) Mitochondrial and sarcoplasmic protein changes in hearts from copper-deficient rats: up-regulation of PGC-1α transcript and protein as a cause for mitochondrial biogenesis in copper deficiency. J Nutr Biochem 20:823–830. https://doi.org/10.1016/j.jnutbio.2008.08.001

    Article  CAS  PubMed  Google Scholar 

  102. Zeng H, Saari JT, Johnson WT (2007) Copper deficiency decreases complex IV but not complex I, II, III, or V in the mitochondrial respiratory chain in rat heart. J Nutr 137:14–18. https://doi.org/10.1093/jn/137.1.14

    Article  CAS  PubMed  Google Scholar 

  103. Johnson WT, Johnson LK (2009) Copper deficiency inhibits Ca2+-induced swelling in rat cardiac mitochondria. J Nutr Biochem 20:248–253. https://doi.org/10.1016/j.jnutbio.2008.02.009

    Article  CAS  PubMed  Google Scholar 

  104. Li Y, Wang L, Schuschke DA, Zhou Z, Saari JT, Kang YJ (2005) Marginal dietary copper restriction induces cardiomyopathy in rats. J Nutr 135:2130–2136. https://doi.org/10.1093/jn/135.9.2130

    Article  CAS  PubMed  Google Scholar 

  105. Jüllig M, Chen X, Hickey AJ, Crossman DJ, Xu A, Wang Y, Greenwood DR, Choong YS, Schönberger SJ, Middleditch MJ, Phillips ARJ, Cooper GJS (2007) Reversal of diabetes-evoked changes in mitochondrial protein expression of cardiac left ventricle by treatment with a copper(II)-selective chelator. Proteomics Clin Appl 1:387–399. https://doi.org/10.1002/prca.200600770

    Article  CAS  PubMed  Google Scholar 

  106. Miller KB, Caton JS, Finley JW (2006) Manganese depresses rat heart muscle respiration. BioFactors 28:33–46. https://doi.org/10.1002/biof.5520280104

    Article  CAS  PubMed  Google Scholar 

  107. Gunter TE, Gerstner B, Lester T, Wojtovich AP, Malecki J, Swarts SG, Brookes PS, Gavin CE, Gunter KK (2010) An analysis of the effects of Mn2+ on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays. Toxicol Appl Pharmacol 249:65–75. https://doi.org/10.1016/j.taap.2010.08.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Van Remmen H, Williams MD, Guo Z et al (2001) Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis. Am J Physiol Circ Physiol 281:H1422–H1432. https://doi.org/10.1152/ajpheart.2001.281.3.H1422

    Article  Google Scholar 

  109. Shen X, Zheng S, Metreveli NS, Epstein PN (2006) Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes 55:798–805. https://doi.org/10.2337/diabetes.55.03.06.db05-1039

    Article  CAS  PubMed  Google Scholar 

  110. Au C, Benedetto A, Aschner M (2008) Manganese transport in eukaryotes: the role of DMT1. Neurotoxicology 29:569–576. https://doi.org/10.1016/j.neuro.2008.04.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258. https://doi.org/10.1152/physrev.00015.2009

    Article  CAS  PubMed  Google Scholar 

  112. Paolisso G, De Riu S, Marrazzo G et al (1991) Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure. Metabolism 40:972–977. https://doi.org/10.1016/0026-0495(91)90075-8

    Article  CAS  PubMed  Google Scholar 

  113. Di NP, Di GP, Gaeta MA et al (2007) Trimetazidine and reduction in mortality and hospitalization in patients with ischemic dilated cardiomyopathy: a post hoc analysis of the Villa Pini DʼAbruzzo Trimetazidine Trial. J Cardiovasc Pharmacol 50:585–589. https://doi.org/10.1097/FJC.0b013e31814fa9cb

    Article  CAS  Google Scholar 

  114. Lopaschuk GD (2003) Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. Circ Res 93:33e–37e. https://doi.org/10.1161/01.RES.0000086964.07404.A5

    Article  CAS  Google Scholar 

  115. Fragasso G, Perseghin G, De Cobelli F et al (2006) Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 27:942–948. https://doi.org/10.1093/eurheartj/ehi816

    Article  CAS  PubMed  Google Scholar 

  116. Mobini R, Fu M, Jansson P-A, Bergh CH, Scharin Täng M, Waagstein F, Andersson B (2006) Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: acute effects of the imidazoline1-receptor agonist moxonidine. Clin Sci 110:329–336. https://doi.org/10.1042/CS20050037

    Article  CAS  Google Scholar 

  117. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ, for the MOXCON Investigators (2003) Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 5:659–667. https://doi.org/10.1016/S1388-9842(03)00163-6

    Article  CAS  PubMed  Google Scholar 

  118. Fragasso G (2016) Deranged cardiac metabolism and the pathogenesis of heart failure. Card Fail Rev 2:8–13. https://doi.org/10.15420/cfr.2016:5:2

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kumar V, Aneesh KA, Kshemada K et al (2017) Amalaki rasayana, a traditional Indian drug enhances cardiac mitochondrial and contractile functions and improves cardiac function in rats with hypertrophy. Sci Rep 7:8588. https://doi.org/10.1038/s41598-017-09225-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Passarella S, Atlante A, Valenti D, de Bari L (2003) The role of mitochondrial transport in energy metabolism. Mitochondrion 2:319–343. https://doi.org/10.1016/S1567-7249(03)00008-4

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the Director, Rajiv Gandhi Centre for Biotechnology, for providing the facilities and funding the study. We thank Ms. Nimmy Francis for the help in the preparation of summary figure and Mr. Aneesh Kumar A for the contribution in the reference style of the manuscript.

Funding

We thank the Department of Science and Technology-Science and Engineering Research Board (DST-SERB), Government of India for funding the study. The study was supported by grants (CO/AB/006/2012) from DST-SERB, Government of India and Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, India.

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Authors and Affiliations

  1. Cardiovascular Diseases and Diabetes Biology group, Rajiv Gandhi Centre for Biotechnology (RGCB), Poojappura, Thycaud Post, Trivandrum, Kerala, 695014, India

    Vikas Kumar, T. R. Santhosh Kumar & C. C. Kartha

  2. Graduate Studies, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India

    Vikas Kumar & T. R. Santhosh Kumar

  3. Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum, Kerala, India

    T. R. Santhosh Kumar

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  1. Vikas Kumar
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  2. T. R. Santhosh Kumar
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VK, TRSK, and CCK designed and directed the overall project. VK wrote and drafted the manuscript. CCK revised and edited the manuscript.

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Correspondence to C. C. Kartha.

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Kumar, V., Santhosh Kumar, T.R. & Kartha, C.C. Mitochondrial membrane transporters and metabolic switch in heart failure. Heart Fail Rev 24, 255–267 (2019). https://doi.org/10.1007/s10741-018-9756-2

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