Skip to main content
SpringerLink
Log in

What Are the Implications of Cr(III) Serving as an Inhibitor of the Beta Subunit of Mitochondrial ATP Synthase?

  • Review
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

A recent report has shown the active site of the beta subunit of mitochondrial ATP synthase is probably the site of action of Cr(III) action, independent of the insulin signaling pathway. This works appears to answer an important question about the mode of action of Cr(III) at a molecular level when supplied in supra-nutritional levels to rodents. However, as with any good research, the research also raises several questions. The relationship between this study and the results of rodent studies of chromium supplementation and between this study and the current understanding the chromium(III) transport and detoxification system are put into perspective.

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

Similar content being viewed by others

Data Availability

No datasets were generated during the current study.

Code Availability

Not applicable.

References

  1. Vincent JB (2013) The Bioinorganic Chemistry of Chromium. Wiley, Chichester

    Google Scholar 

  2. Wang H, Hu L, Li H, Lai Y-T, Wei X, Xu X, Cao Z, Cao H, Wan Q, Chang Y-Y, Xu A, Zhou Q, Jiang G, He M-L, Sun H (2023) Mitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemic stress. Nature Commun 14:1738

    Article  ADS  Google Scholar 

  3. Donaldson DL, Lee DM, Smith CC, Rennert OM (1985) Glucose tolerance and plasma lipid distributions in rats fed a high-sucrose, high-cholesterol, low-chromium diet. Metabolism 34:1086–1093

    Article  CAS  PubMed  Google Scholar 

  4. Jain R, Verch RL, Wallach S, Peabody RA (1981) Tissue chromium exchange in the rat. Am J Clin Nutr 34:2199–2204

    Article  CAS  PubMed  Google Scholar 

  5. Flatt PR, Juntti-Berggren L, Beggren P-O, Gould BJ, Swanston-Flatt SK (1989) Effects of dietary inorganic trivalent chromium (Cr) on the development of glucose homeostasis in rats. Diabete Metab 15:93–97

    CAS  PubMed  Google Scholar 

  6. National Research Council (2002) Dietary Reference Intakes for Vitamin A, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. A report of the Panel of Micronutrients, Subcommittee on Upper Reference Levels of Nutrients and of Interpretations and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. National Academy of Sciences, Washington, DC

  7. Striffler JS, Law JS, Polansky MM, Bhathena SJ, Anderson RA (1995) Chromium improves insulin response to glucose in rats. Metabolism 44:1314–1320

    Article  CAS  PubMed  Google Scholar 

  8. Striffler JS, Polansky MM, Anderson RA (1998) Dietary chromium decreases insulin resistance in rats fed a high-fat, mineral-imbalanced diet. Metabolism 47:396–400

    Article  CAS  PubMed  Google Scholar 

  9. Striffer JS, Polansky MM, Anderson RA (1999) Overproduction of insulin in the chromium-deficient rat. Metabolism 48:1063–1068

    Article  Google Scholar 

  10. Di Bona KR, Love S, Rhodes NR, McAdory D, Sinha SH, Kern N, Kent J, Strickland J, Wilson A, Beaird J, Ramage J, Rasco JF, Vincent JB (2011) Chromium is not an essential trace element for mammals: effects of a “low-chromium” diet. J Biol Inorg Chem 16:381–390

    Article  PubMed  Google Scholar 

  11. Bertinato J, Griffin P (2023) A low chromium diet increases body fat, energy intake and circulating triglycerides and insulin in male and female rats fed a moderately high-fat, high-sucrose diet from puberty to adult young age. PLoS One 18:e0281019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun Y, Clodfelder BJ, Shute AA, Irvin T, Vincent JB (2002) The biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ decreases plasma insulin, cholesterol and triglycerides in healthy and type II but not type I diabetic rats. J Biol Inorg Chem 7:852–862

    Article  CAS  PubMed  Google Scholar 

  13. Sun Y, Mallya K, Ramirez J, Vincent JB (1999) The biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ decreases plasma cholesterol and triglycerides in rat: Towards chromium-containing therapeutics. J Biol Inorg Chem 4:838–845

    Article  CAS  PubMed  Google Scholar 

  14. Clodfelder BJ, Gullick BM, Lukaski HC, Neggers Y, Vincent JB (2005) Oral administration of the biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ increases insulin sensitivity and improves blood plasma variables in healthy and type 2 diabetic rats. J Biol Inorg Chem 10:119–130

    Article  CAS  PubMed  Google Scholar 

  15. Bennett R, Adams B, French A, Neggers Y, Vincent JB (2006) High dose chromium(III) supplementation has no effects on body mass and composition while altering plasma hormone and cholesterol levels. Biol Trace Elem Res 113:53–66

    Article  CAS  PubMed  Google Scholar 

  16. Krol E, Krejpcio Z (2011) Evaluation of antidiabetic potential of chromium(III) propionate complex in streptozotocin-induced experimental diabetes. Food Chem Toxicol 49:3217–3223

    Article  CAS  PubMed  Google Scholar 

  17. Krol E, Krejpcio Z (2010) Chromium(III) propionate complex supplementation improves carbohydrate metabolism in insulin-resistance rat model. Food Chem Toxicol 48:2791–2796

    Article  CAS  PubMed  Google Scholar 

  18. Vincent JB (2014) Is chromium pharmacologically relevant? J Trace Elem Med Biol 28:397–405

    Article  CAS  PubMed  Google Scholar 

  19. Vincent JB (2019) Effects of chromium supplementation on body composition, human and animal health, and insulin and glucose metabolism. Curr Opin Clin Nutr Metab Care 22:483–489

    Article  CAS  PubMed  Google Scholar 

  20. Wang ZQ, Zhang XH, Russell JC, Hulver M, Cefalu WT (2005) Chromium picolinate enhances skeletal muscle cellular insulin signaling in vivo in obese, insulin-resistant JCR:LA-cp rats. J Nutr 136:415–420

    Article  Google Scholar 

  21. Wang H, Kruszewski A, Brautigan DL (2005) Cellular chromium enhances activation of insulin receptor kinase. Biochemistry 44:8167–8175

    Article  CAS  PubMed  Google Scholar 

  22. Brautigan DL, Kruszewski A, Wang H (2006) Chromium and vanadate combination increases insulin-induced glucose uptake by 3T#-L1 adipocytes. Biochem Biophys Res Commun 347:769–773

    Article  CAS  PubMed  Google Scholar 

  23. Miranda ER, Dey CS (2004) Effect of chromium and zinc on insulin signaling in skeletal muscle cells. Biol Trace Elem Res 101:19–36

    Article  CAS  PubMed  Google Scholar 

  24. Yang X, Palanichamy K, Ontko AC, Rao MNA, Fang CX, Ren J, Sreejayan N (2005) A newly synthesized chromium complex – chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance. FEBS Lett 579:1458–1464

    Article  CAS  PubMed  Google Scholar 

  25. Dong F, Yang X, Sreejayan N, Run J (2007) Chromium (D-phenylalanine)3 improves obesity-induced cardiac contractile defect in ob/ob mice. Obesity 15:2699–2711

    Article  CAS  PubMed  Google Scholar 

  26. Pattar GR, Tackett L, Liu P, Elmendorf JS (2206) Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions. Mutat Res 610:93–100

  27. Hoffman NJ, Penque BA, Habegger KM, Sealls W, Tackett L, Elmendorf JS (2014) Chromium enhances insulin responsiveness via AMPK. J Nutr Biochem 25:565–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yamamoto A, Wada O, Ono T (1987) Isolation of a biologically active low-molecular-mass chromium compound from rabbit liver. Eur J Biochem 165:627–631

    Article  CAS  PubMed  Google Scholar 

  29. Yamamoto A, Wada O, Suzuki H (1988) Purification and properties of biologically active chromium complex from bovine colostrum. J Nutr 118:39–45

    Article  CAS  PubMed  Google Scholar 

  30. Vincent JB (1994) Relationship between glucose tolerance factor and low-molecular-weight chromium-binding substance. J Nutr 124:117–118

    Article  CAS  PubMed  Google Scholar 

  31. Davis CM, Vincent JB (1997) Chromium oligopeptide activates insulin receptor kinase activity. Biochemistry 36:4382–4385

    Article  CAS  PubMed  Google Scholar 

  32. Vincent JB (2000) The biochemistry of chromium. J Nutr 130:715–718

    Article  CAS  PubMed  Google Scholar 

  33. Vincent JB (2000) Elucidating a biological role for chromium at a molecular level. Acc Chem Res 33:503–510

    Article  CAS  PubMed  Google Scholar 

  34. Goldstein BJ, Zhu L, Hager R, Zilbering A, Sun Y, Vincent JB (2001) Enhancement of post-receptor insulin signaling by trivalent chromium in hepatoma cells is associated with differential inhibition of specific protein-tyrosine phosphatases. J Trace Elem Exp Med 14:93–404

    Article  Google Scholar 

  35. Davis CM, Sumrall KH, Vincent JB (1996) A biologically active form of chromium may activate a membrane phosphotyrosine phosphatase (PTP). Biochemistry 35:12963–12969

    Article  CAS  PubMed  Google Scholar 

  36. Deng G, Wu K, Cruce A, Bowman MW, Vincent JB (2015) Binding of trivalent chromium to serum transferrin is sufficiently rapid to be physiologically relevant. J Inorg Biochem 143:48–55

    Article  CAS  PubMed  Google Scholar 

  37. Edwards KC, Kim H, Vincent JB (2020) Release of trivalent chromium from serum transferrin is sufficiently rapid to be physiologically relevant. J Inorg Biochem 202:110901

    Article  CAS  PubMed  Google Scholar 

  38. Edwards KC, Kim H, Ferguson R, Lockart VJB (2020) Significance of conformational changes during the binding and release of chromium(III) from human serum transferrin. J Inorg Biochem 206:111040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Edwards KC, Gannon MW, Frantom PA, Vincent JB (2021) Low-molecular-weight chromium-binding substance (LMWCr) may bind and carry Cr(III) from the endosome. J Inorg Biochem 223:111555

    Article  CAS  PubMed  Google Scholar 

  40. Sun Y, Ramirez J, Woski SA, Vincent JB (2000) the binding of trivalent chromium to low-molecular-weight chromium-binding substance (LMWCr) and the transfer of chromium from transferrin and Cr(pic)3 to LMWCr. J Biol Inorg Chem 5:129–136

    Article  CAS  PubMed  Google Scholar 

  41. Jacquamet L, Sun Y, Hatfield J, Gu W, Cramer SP, Crowder MW, Lorigan GA, Vincent JB, Latour J-M (2003) Characterization of chromodulin by X-ray absorption and electron paramagnetic resonance spectroscopies and magnetic susceptibility measurements. J Am Chem Soc 125:774–780

    Article  CAS  PubMed  Google Scholar 

  42. Costello RB, Dwyer JT, Merkel JM (2019) Chromium supplements in health and disease. In: Vincent JBJ (ed) The Nutritional Biochemistry of Chromium, 2nd edn. Elsevier, Amsterdam, pp 219–249

    Chapter  Google Scholar 

  43. Gullick, BM (2005) Characterizing the potential therapeutic agent [Cr3O(O2CCH2CH3)6(H2O)3]+: Its uptake and subcellular distribution and the effects of its oral administration on blood variables. Ph.D. dissertation, The University of Alabama

  44. Clodfelder BJ, Emamaullee J, Hepburn DDD, Chakov NE, Nettles HS, Vincent JB (2001) The trail of chromium(III) in vivo from the blood to the urine: The roles of transferrin and chromodulin. J Biol Inorg Chem 6:608–617

    Article  CAS  PubMed  Google Scholar 

  45. Clodfelder BJ, Upchurch RG, Vincent JB (2004) A comparison of the insulin-sensitive transport of chromium in healthy and model diabetic rats. J Inorg Biochem 98:522–533

    Article  CAS  PubMed  Google Scholar 

  46. Clodfelder BJ, Vincent JB (2005) The time-dependent transport of chromium in adult rats from the bloodstream to the urine. J Biol Inorg Chem 10:383–393

    Article  CAS  PubMed  Google Scholar 

  47. Danenberg KD, Cleland WW (1975) Use of chromium-adenosine triphosphate and lyxose to elucidate the kinetic mechanism and coordination state of the nucleotide substrate for yeast hexokinase. Biochemistry 14:28–39

    Article  CAS  PubMed  Google Scholar 

  48. Bossard MJ, Schuster SM (1981) Structural preferences for the binding of chromium nucleotides by beef heart mitochondrial ATPase. J Biol Chem 256:6617–6622

    Article  CAS  PubMed  Google Scholar 

  49. Schuster SM, Ebel RE, Lardy HA (1975) Kinetic studies on rat liver and beef heart mitochondrial adenosine triphosphate: The effects of the chromium complexes of adenosine triphosphate and adenosine diphosphate on the kinetic properties. Arch Biochem Biophys 171:656–661

    Article  CAS  PubMed  Google Scholar 

  50. Mulkani L, Levina A, Lay PA (2004) Biomimetic oxidation of chromium(III): Does the antidiabetic activity of chromium(III) involve carcinogenic chromium(VI)? Angew Chem Int Ed 43:4504–4507

    Article  Google Scholar 

  51. Levina A, Lay PA (2005) mechanistic studies of relevance to the biological activities of chromium. Coord Chem Rev 249:281–298

    Article  CAS  Google Scholar 

  52. Cocheme HM, Quin C, McQuaker SJ, Cabreiro F, Logan A, Prime TA, Abakumova I, Patel JV, Fearnley IM, James AM, Porteous CM, Smith RAJ, Saeed S, Carre JE, Singer M, Gems D, Hartley RC, Partridge L, Murphy MP (2011) Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab 13:340–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stein KT, Moon SJ, Nguyen AN, Sikes HD (2020) Kinetic modeling of H2O2 dynamics in the mitochondria of HeLa cells. PLoS Comput Biol 16:e1008202

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. de Cubas L, Pak VV, Belousov VV, Ayte J, Hidalgo E (2021) The mitochondria-to-cytosol H2O2 gradient is caused by peroxiredoxin-dependent cytosolic scavenging. Antioxidants 10:731

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Institutes of Health, R15ES033800 (to J.B.V).

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, AL, 35487-0336, USA

    John B. Vincent

Authors
  1. John B. Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.B.V. is responsible for all aspects of this manuscript.

Corresponding author

Correspondence to John B. Vincent.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics Approval

Not applicable.

Conflict of Interest

The author declares no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vincent, J.B. What Are the Implications of Cr(III) Serving as an Inhibitor of the Beta Subunit of Mitochondrial ATP Synthase?. Biol Trace Elem Res 202, 1335–1344 (2024). https://doi.org/10.1007/s12011-023-03809-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-023-03809-7

Keywords

Search

Navigation