Skip to content
naulon

No retraction, correction or concern found when last checked on Oct 31, 2026.

The Bioenergetic Health Index: a new concept in mitochondrial translational research

Balu K. Chacko, Philip A. Kramer, Saranya Ravi and 11 more

Clinical Science · 2014 · Review · CC BY-NC

doi:10.1042/cs20140101

Abstract

Bioenergetics has become central to our understanding of pathological mechanisms, the development of new therapeutic strategies and as a biomarker for disease progression in neurodegeneration, diabetes, cancer and cardiovascular disease. A key concept is that the mitochondrion can act as the ‘canary in the coal mine’ by serving as an early warning of bioenergetic crisis in patient populations. We propose that new clinical tests to monitor changes in bioenergetics in patient populations are needed to take advantage of the early and sensitive ability of bioenergetics to determine severity and progression in complex and multifactorial diseases. With the recent development of high-throughput assays to measure cellular energetic function in the small number of cells that can be isolated from human blood these clinical tests are now feasible. We have shown that the sequential addition of well-characterized inhibitors of oxidative phosphorylation allows a bioenergetic profile to be measured in cells isolated from normal or pathological samples. From these data we propose that a single value–the Bioenergetic Health Index (BHI)–can be calculated to represent the patient's composite mitochondrial profile for a selected cell type. In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes. We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 49

  1. 1.

    Sundstrom J., Riserus U., Byberg L., Zethelius B., Lithell H., Lind L. Clinical value of the metabolic syndrome for long term prediction of total and cardiovascular mortality: prospective, population based cohort study. BMJ. 2006;332:878-882.

    Not in our library10.1136/bmj.38766.624097.1f

  2. 2.

    Blake R., Trounce I. A. Mitochondrial dysfunction and complications associated with diabetes. Biochim. Biophys. Acta. 2013;1840:1404-1412.

    Not in our library10.1016/j.bbagen.2013.11.007

  3. 3.

    Ilkun O., Boudina S. Cardiac dysfunction and oxidative stress in the metabolic syndrome: an update on antioxidant therapies. Curr. Pharm. Des. 2013;19:4806-4817.

    Not in our library10.2174/1381612811319270003

  4. 4.

    Caimari A., Oliver P., Keijer J., Palou A. Peripheral blood mononuclear cells as a model to study the response of energy homeostasis-related genes to acute changes in feeding conditions. OMICS. 2010;14:129-141.

    Not in our library10.1089/omi.2009.0092

  5. 5.

    Japiassu A. M., Santiago A. P., d’Avila J. C., Garcia-Souza L. F., Galina A., Castro Faria-Neto H. C., Bozza F. A., Oliveira M. F. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5′-triphosphate synthase activity. Crit. Care Med. 2011;39:1056-1063.

    Not in our library10.1097/ccm.0b013e31820eda5c

  6. 6.

    Sternfeld T., Tischleder A., Schuster M., Bogner J. R. Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV-1 infected patients. HIV Med. 2009;10:512-519.

    Not in our library10.1111/j.1468-1293.2009.00723.x

  7. 7.

    Shikuma C. M., Gerschenson M., Chow D., Libutti D. E., Willis J. H., Murray J., Capaldi R. A., Marusich M. Mitochondrial oxidative phosphorylation protein levels in peripheral blood mononuclear cells correlate with levels in subcutaneous adipose tissue within samples differing by HIV and lipoatrophy status. AIDS Res. Hum. Retroviruses. 2008;24:1255-1262.

    Not in our library10.1089/aid.2007.0262

  8. 8.

    Korsten A., de Coo I. F., Spruijt L., de Wit L. E., Smeets H. J., Sluiter W. Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation. Biochim. Biophys. Acta. 2010;1797:197-203.

    Not in our library10.1016/j.bbabio.2009.10.003

  9. 9.

    Chacko B. K., Kramer P. A., Ravi S., Johnson M. S., Hardy R. W., Ballinger S. W., Darley-Usmar V. M. Methods for defining distinct bioenergetic profiles in platelets, lympho-cytes, monocytes, and neutrophils, and the oxidative burst from human blood. Lab. Invest. 2013;93:690-700.

    Not in our library10.1038/labinvest.2013.53

  10. 10.

    Dranka B. P., Benavides G. A., Diers A. R., Giordano S., Zelickson B. R., Reily C., Zou L. Y., Chatham J. C., Hill B. G., Zhang J. H., et al. Assessing bioenergetic function in response to oxidative stress by metabolic profiling. Free Radic. Biol. Med. 2011;51:1621-1635.

    Not in our library10.1016/j.freeradbiomed.2011.08.005

  11. 11.

    Nicholls D. G., Darley-Usmar V. M., Wu M., Jensen P. B., Rogers G. W., Ferrick D. A. Bioenergetic profile experiment using C2C12 myoblast cells. J. Vis. Exp. 2010;2010:2511.

    Not in our library10.3791/2511

  12. 12.

    Hill B. G., Benavides G. A., Lancaster J. R., Ballinger S., Dell’Italia L., Jianhua Z., Darley-Usmar V. M. Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol. Chem. 2012;393:1485-1512.

    Not in our library10.1515/hsz-2012-0198

  13. 13.

    Avila C., Huang R. J., Stevens M. V., Aponte A. M., Tripodi D., Kim K. Y., Sack M. N. Platelet mitochondrial dysfunction is evident in type 2 diabetes in association with modifications of mitochondrial anti-oxidant stress proteins. Exp. Clin. Endocrinol. Diabetes. 2012;120:248-251.

    Not in our library10.1055/s-0031-1285833

  14. 14.

    Zharikov S., Shiva S. Platelet mitochondrial function: from regulation of thrombosis to biomarker of disease. Biochem. Soc. Trans. 2013;41:118-123.

    Not in our library10.1042/bst20120327

  15. 15.

    Caldwell S. H., Swerdlow R. H., Khan E. M., Iezzoni J. C., Hespenheide E. E., Parks J. K., Parker W. D. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J. Hepatol. 1999;31:430-434.

    Not in our library10.1016/s0168-8278(99)80033-6

  16. 16.

    Schapira A. H., Gu M., Taanman J. W., Tabrizi S. J., Seaton T., Cleeter M., Cooper J. M. Mitochondria in the etiology and pathogenesis of Parkinson's disease. Ann. Neurol. 1998;44:S89-98.

    Not in our library10.1002/ana.410440714

  17. 17.

    Murphy M. P. Targeting lipophilic cations to mitochondria. Biochim. Biophys. Acta. 2008;1777:1028-1031.

    Not in our library10.1016/j.bbabio.2008.03.029

  18. 18.

    Dranka B. P., Hill B. G., Darley-Usmar V. M. Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radic. Biol. Med. 2010;48:905-914.

    Not in our library10.1016/j.freeradbiomed.2010.01.015

  19. 19.

    Benavides G. A., Liang Q., Dodson M., Darley-Usmar V., Zhang J. Inhibition of autophagy and glycolysis by nitric oxide during hypoxia-reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons. Free Radic. Biol. Med. 2013;65:1215-1228.

    Not in our library10.1016/j.freeradbiomed.2013.09.006

  20. 20.
  21. 21.

    Schneider L., Giordano S., Zelickson B. R., M S. J., G A. B., Ouyang X., Fineberg N., Darley-Usmar V. M., Zhang J. Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress. Free Radic. Biol. Med. 2011;51:2007-2017.

    Not in our library10.1016/j.freeradbiomed.2011.08.030

  22. 22.

    Brand M. D., Nicholls D. G. Assessing mitochondrial dysfunction in cells. Biochem. J. 2011;435:297-312.

    Not in our library10.1042/bj20110162

  23. 23.

    Kingsley-Hickman P. B., Sako E. Y., Ugurbil K., From A. H., Foker J. E. 31P NMR measurement of mitochondrial uncoupling in isolated rat hearts. J. Biol. Chem. 1990;265:1545-1550.

    Not in our library

  24. 24.

    Gong G., Liu J., Liang P., Guo T., Hu Q., Ochiai K., Hou M., Ye Y., Wu X., Mansoor A., et al. Oxidative capacity in failing hearts. Am. J. Physiol. Heart Circ. Physiol. 2003;285:H541-H548.

    Not in our library10.1152/ajpheart.01142.2002

  25. 25.

    Zelickson B. R., Benavides G. A., Johnson M. S., Chacko B. K., Venkatraman A., Landar A., Betancourt A. M., Bailey S. M., Darley-Usmar V. M. Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes. Biochim. Biophys. Acta. 2011;1807:1573-1582.

    Not in our library10.1016/j.bbabio.2011.09.011

  26. 26.

    Sansbury B. E., Jones S. P., Riggs D. W., Darley-Usmar V. M., Hill B. G. Bioenergetic function in cardiovascular cells: the importance of the reserve capacity and its biological regulation. Chem. Biol. Interact. 2011;191:288-295.

    Not in our library10.1016/j.cbi.2010.12.002

  27. 27.

    Hill B. G., Dranka B. P., Zou L., Chatham J. C., Darley-Usmar V. M. Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal. Biochem. J. 2009;424:99-107.

    Not in our library10.1042/bj20090934

  28. 28.

    Tavakoli S., Zamora D., Ullevig S., Asmis R. Bioenergetic profiles diverge during macrophage polarization: implications for the interpretation of 18F-FDG PET imaging of atherosclerosis. J. Nucl. Med. 2013;54:1661-1667.

    Not in our library10.2967/jnumed.112.119099

  29. 29.

    van der Windt G. J., Everts B., Chang C. H., Curtis J. D., Freitas T. C., Amiel E., Pearce E. J., Pearce E. L. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36:68-78.

    Not in our library10.1016/j.immuni.2011.12.007

  30. 30.

    Dodson M., Liang Q., Johnson M. S., Redmann M., Fineberg N., Darley-Usmar V. M., Zhang J. Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells. Autophagy. 2013;9:1996-2008.

    Not in our library10.4161/auto.26094

  31. 31.

    Perrin S., Cremer J., Roll P., Faucher O., Menard A., Reynes J., Dellamonica P., Naqvi A., Micallef J., Jouve E., et al. HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 “Aging” study. PLoS ONE. 2012;7:e41129.

    Not in our library10.1371/journal.pone.0041129

  32. 32.

    Widlansky M. E., Wang J., Shenouda S. M., Hagen T. M., Smith A. R., Kizhakekuttu T. J., Kluge M. A., Weihrauch D., Gutterman D. D., Vita J. A. Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes. Transl. Res. 2010;156:15-25.

    Not in our library10.1016/j.trsl.2010.04.001

  33. 33.

    Wynn T. A., Chawla A., Pollard J. W. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445-455.

    Not in our library10.1038/nature12034

  34. 34.

    Tugal D., Liao X., Jain M. K. Transcriptional control of macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 2013;33:1135-1144.

    Not in our library10.1161/atvbaha.113.301453

  35. 35.

    Zhou D., Huang C., Lin Z., Zhan S., Kong L., Fang C., Li J. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell. Signal. 2013;26:192-197.

    Not in our library10.1016/j.cellsig.2013.11.004

  36. 36.

    Krauss S., Brand M. D., Buttgereit F. Signaling takes a breath–new quantitative perspectives on bioenergetics and signal transduction. Immunity. 2001;15:497-502.

    Not in our library10.1016/s1074-7613(01)00205-9

  37. 37.

    Pearce E. L., Poffenberger M. C., Chang C. H., Jones R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454.

    Not in our library10.1126/science.1242454

  38. 38.

    Pearce E. L., Pearce E. J. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38:633-643.

    Not in our library10.1016/j.immuni.2013.04.005

  39. 39.

    van der Windt G. J., Pearce E. L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 2012;249:27-42.

    Not in our library10.1111/j.1600-065x.2012.01150.x

  40. 40.

    Macintyre A. N., Rathmell J. C. Activated lymphocytes as a metabolic model for carcinogenesis. Cancer Metab. 2013;1:5.

    Not in our library10.1186/2049-3002-1-5

  41. 41.

    Reuter H., Gross R. Platelet metabolism. Suppl. Thromb. Haemost. 1978;63:87-95.

    Not in our library

  42. 42.

    Medina-Gomez G. Mitochondria and endocrine function of adipose tissue. Best Pract. Res. Clin. Endocrinol. Metab. 2012;26:791-804.

    Not in our library10.1016/j.beem.2012.06.002

  43. 43.

    Patel P. S., Buras E. D., Balasubramanyam A. The role of the immune system in obesity and insulin resistance. J. Obes. 2013;2013:616193.

    Not in our library10.1155/2013/616193

  44. 44.

    Fetterman J. L., Pompilius M., Westbrook D. G., Uyeminami D., Brown J., Pinkerton K. E., Ballinger S. W. Developmental exposure to second-hand smoke increases adult atherogenesis and alters mitochondrial DNA copy number and deletions in apoE−/− mice. PLoS ONE. 2013;8:e66835.

    Not in our library10.1371/journal.pone.0066835

  45. 45.

    Krzywanski D. M., Moellering D. R., Fetterman J. L., Dunham-Snary K. J., Sammy M. J., Ballinger S. W. The mitochondrial paradigm for cardiovascular disease susceptibility and cellular function: a complementary concept to Mendelian genetics. Lab. Invest. 2011;91:1122-1135.

    Not in our library10.1038/labinvest.2011.95

  46. 46.

    Cakir Y., Yang Z., Knight C. A., Pompilius M., Westbrook D., Bailey S. M., Pinkerton K. E., Ballinger S. W. Effect of alcohol and tobacco smoke on mtDNA damage and atherogenesis. Free Radic. Biol. Med. 2007;43:1279-1288.

    Not in our library10.1016/j.freeradbiomed.2007.07.015

  47. 47.

    Wallace D. C. Bioenergetic Origins of Complexity and Disease. Cold Spring Harb. Symp. Quant. Biol. 2011;76:1-16.

    Not in our library10.1101/sqb.2011.76.010462

  48. 48.

    Wallace D. C. Mitochondrial DNA mutations in disease and aging. Environ. Mol. Mutagen. 2010;51:440-450.

    Not in our library10.1002/em.20586

  49. 49.

    Dunham-Snary K. J., Ballinger S. W. Mitochondrial genetics and obesity: evolutionary adaptation and contemporary disease susceptibility. Free Radic. Biol. Med. 2013;65:1229-1237.

    Not in our library10.1016/j.freeradbiomed.2013.09.007

Cited by papers we hold 8

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.