Inhibitory Properties of Ruthenium Amine Complexes on Mitochondrial Calcium Uptake

Overview

Journal J Bioenerg Biomembr

Publisher Springer

Specialties Biochemistry
Biology
Endocrinology

Date 2000 Feb 22

PMID 10682913

Citations 27

Authors

C Zazueta

M E Sosa-Torres

F Correa

Affiliations

Soon will be listed here.

Abstract

The recent finding that the inhibition of Ca2+-stimulated respiration by ruthenium red is mainly due to a binuclear ruthenium complex (Ru360) present in the commercial samples of the classical inhibitor ruthenium red (Ying et. al., 1991), showed that this complex is the more potent and specific inhibitor of the mitochondrial calcium uniporter. This work was aimed to provide insights into the mechanism by which Ru360 and other ruthenium-related compounds inhibits calcium uptake. Ruthenium red and a synthesized analog (Rrphen) were compared with Ru360. The inhibition by this binuclear complex was noncompetitive, with a Ki of 9.89 nM. The number of specific binding sites for Ru360 was 6.2 pmol/mg protein. Ruthenium red and Ru360 were mutually exclusive inhibitors. Bound La3+ was not displaced by Ru360. Rrphen was the least effective for inhibiting calcium uptake. The results support the notion of a specific binding site in the uniporter for the polycationic complexes and a negative charged region from the phospholipids in the membrane, closely associated with the uniporter inhibitor-binding site.

Citing Articles

Toward the Treatment of Glioblastoma Tumors Using Photoactivated Chemotherapy: In Vitro Evaluation of Efficacy and Safety.

Goetzfried S, Hakkennes M, Busemann A, Bonnet S ACS Pharmacol Transl Sci. 2025; 8(2):484-498.

PMID: 39974641 PMC: 11833736. DOI: 10.1021/acsptsci.4c00600.

Increased mitochondrial free Ca during ischemia is suppressed, but not eliminated by, germline deletion of the mitochondrial Ca uniporter.

Petersen C, Sun J, Silva K, Kosmach A, Balaban R, Murphy E Cell Rep. 2023; 42(7):112735.

PMID: 37421627 PMC: 10529381. DOI: 10.1016/j.celrep.2023.112735.

Alternative Targets for Modulators of Mitochondrial Potassium Channels.

Wrzosek A, Galecka S, Zochowska M, Olszewska A, Kulawiak B Molecules. 2022; 27(1).

PMID: 35011530 PMC: 8746388. DOI: 10.3390/molecules27010299.

Mitochondrial calcium exchange in physiology and disease.

Garbincius J, Elrod J Physiol Rev. 2021; 102(2):893-992.

PMID: 34698550 PMC: 8816638. DOI: 10.1152/physrev.00041.2020.

Machine learning-based classification of mitochondrial morphology in primary neurons and brain.

Fogo G, Anzell A, Maheras K, Raghunayakula S, Wider J, Emaus K Sci Rep. 2021; 11(1):5133.

PMID: 33664336 PMC: 7933342. DOI: 10.1038/s41598-021-84528-8.

References

Zazueta C, Zafra G, Vera G, Sanchez C, Chavez E . Advances in the purification of the mitochondrial Ca2+ uniporter using the labeled inhibitor 103Ru360. J Bioenerg Biomembr. 1999; 30(5):489-98. DOI: 10.1023/a:1020546331217. View

Tashmukhamedov B, Gagelgans A, Mamatkulov K, Makhmudova E . Inhibition of Ca(2+) transport in mitochondria by selective blockade of membrane mucopolysaccharides by hexamine cobaltichloride. FEBS Lett. 1972; 28(2):239-242. DOI: 10.1016/0014-5793(72)80721-x. View

Sparagna G, Gunter K, Sheu S, GUNTER T . Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J Biol Chem. 1995; 270(46):27510-5. DOI: 10.1074/jbc.270.46.27510. View

YAMADA E, Huzel N . The calcium-binding ATPase inhibitor protein from bovine heart mitochondria. Purification and properties. J Biol Chem. 1988; 263(23):11498-503. View

Matlib M, Zhou Z, Knight S, Ahmed S, Choi K, Phillips R . Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes. J Biol Chem. 1998; 273(17):10223-31. DOI: 10.1074/jbc.273.17.10223. View

Halestrap A . The regulation of the oxidation of fatty acids and other substrates in rat heart mitochondria by changes in the matrix volume induced by osmotic strength, valinomycin and Ca2+. Biochem J. 1987; 244(1):159-64. PMC: 1147967. DOI: 10.1042/bj2440159. View

VOELKER D, Smejtek P . Adsorption of ruthenium red to phospholipid membranes. Biophys J. 1996; 70(2):818-30. PMC: 1224982. DOI: 10.1016/S0006-3495(96)79621-2. View

LUFT J . Ruthenium red and violet. I. Chemistry, purification, methods of use for electron microscopy and mechanism of action. Anat Rec. 1971; 171(3):347-68. DOI: 10.1002/ar.1091710302. View

Litsky M, Pfeiffer D . Regulation of the mitochondrial Ca2+ uniporter by external adenine nucleotides: the uniporter behaves like a gated channel which is regulated by nucleotides and divalent cations. Biochemistry. 1997; 36(23):7071-80. DOI: 10.1021/bi970180y. View

10.

White R, Reynolds I . Mitochondria and Na+/Ca2+ exchange buffer glutamate-induced calcium loads in cultured cortical neurons. J Neurosci. 1995; 15(2):1318-28. PMC: 6577803. View

11.

McCormack J, Halestrap A, Denton R . Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev. 1990; 70(2):391-425. DOI: 10.1152/physrev.1990.70.2.391. View

12.

Moreno-Sanchez R . Regulation of oxidative phosphorylation in mitochondria by external free Ca2+ concentrations. J Biol Chem. 1985; 260(7):4028-34. View

13.

Carrondo M, Griffith W, Hall J, Skapski A . X-ray structure of [Ru3 O2 (NH3)14]6+, cation of the cytological reagent Ruthenium Red. Biochim Biophys Acta. 1980; 627(3):332-4. DOI: 10.1016/0304-4165(80)90464-x. View

14.

Ying W, Emerson J, Clarke M, SANADI D . Inhibition of mitochondrial calcium ion transport by an oxo-bridged dinuclear ruthenium ammine complex. Biochemistry. 1991; 30(20):4949-52. DOI: 10.1021/bi00234a016. View

15.

Missiaen L, De Smedt H, Droogmans G, Wuytack F, Raeymaekers L, Casteels R . Ruthenium red and compound 48/80 inhibit the smooth-muscle plasma-membrane Ca2+ pump via interaction with associated polyphosphoinositides. Biochim Biophys Acta. 1990; 1023(3):449-54. DOI: 10.1016/0005-2736(90)90138-e. View

16.

Reed K, Bygrave F . The inhibition of mitochondrial calcium transport by lanthanides and ruthenium red. Biochem J. 1974; 140(2):143-55. PMC: 1167986. DOI: 10.1042/bj1400143. View

17.

Gibson J, Poole R, Hughes M, Rees J . A dimeric complex of ruthenium: a new inhibitor of respiration-driven calcium transport in Escherichia coli K12. J Gen Microbiol. 1982; 128(9):2211-4. DOI: 10.1099/00221287-128-9-2211. View

18.

Hansford R . Physiological role of mitochondrial Ca2+ transport. J Bioenerg Biomembr. 1994; 26(5):495-508. DOI: 10.1007/BF00762734. View

19.

Rizzuto R, Brini M, Murgia M, Pozzan T . Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science. 1993; 262(5134):744-7. DOI: 10.1126/science.8235595. View

20.

Panov A, Scaduto Jr R . Influence of calcium on NADH and succinate oxidation by rat heart submitochondrial particles. Arch Biochem Biophys. 1995; 316(2):815-20. DOI: 10.1006/abbi.1995.1109. View