The inhibition of calcium uptake and release by rat liver mitochondria by ruthenium red

Luthra, Rajyalakshmi; Olson, Merle S.

doi:10.1016/0014-5793(77)80947-2

Cited by 29 publications

(14 citation statements)

References 11 publications

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“…Further evidence that the mechanism of Ca2+ efflux seen in the present report differs from that occurring in the presence of Pi was the finding that Mg2+ and Ruthenium Red, each of which inhibits Ca2+ efflux in the presence of Pi (Ernster, 1956;Haugaard et al, 1969a;Sordahl, 1974;Luthra & Olson, 1977;Carafoli et al, 1977), were ineffective in preventing Ca2+ efflux under the present incubation conditions. Moreover, other experiments in this laboratory (V. Prpic, T. L. Spencer & F. L. Bygrave, unpublished work) have shown that glucagon administration to rats in vivo, which offsets the uncoupling action of Ca2+ on isolated mitochondria described above, is without effect on the Ca2+ efflux seen here (see also Dorman et al, 1975).…”

Section: Discussioncontrasting

confidence: 47%

“…2(b) provide the second piece of evidence that Ca2+ efflux occurring in the absence of Pi cycling is different from that occurring in its presence. Ruthenium Red, which is reported to prevent Ca2+ efflux from mitochondria when Pi is present (Carafoli et al, 1977;Luthra & Olson, 1977), had no effect on that occurring when N-ethylmaleimide is first preincubated with the mitochondria.…”

Section: Resultsmentioning

confidence: 90%

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Calcium ion cycling in rat liver mitochondria

Ramachandran

Bygrave

1978

Biochemical Journal

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1. Addition of N-ethylmaleimide to rat liver mitochondria respiring with succinate as substrate decreases both the initial rate of Ca(2+) transport and the ability of mitochondria to retain Ca(2+). As a result, Ca(2+) begins to leave the mitochondria soon after it has entered. Half-maximal effects occur at an N-ethylmaleimide concentration of about 100nmol/mg of protein. 2. The efflux of Ca(2+) induced by N-ethylmaleimide is not prevented by Mg(2+) or by Ruthenium Red at concentrations known to prevent Ca(2+) efflux when exogenous phosphate also is present. Swelling of mitochondria does not accompany N-ethylmaleimide-induced Ca(2+) efflux. 3. Addition of Ca(2+) to rat liver mitochondria in the presence of N-ethylmaleimide produces an immediate decrease in DeltaE (membrane potential), which decreases further to only a slight extent over the next 8min. Concomitant with this is an immediate increase and then levelling off of the -59DeltapH (transmembrane pH gradient). 4. Preincubation of rat liver mitochondria with p-chloromercuribenzenesulphonate, which by contrast with N-ethylmaleimide is unable to penetrate the inner mitochondrial membrane, also prevents Ca(2+) retention. The DeltaE and -59DeltapH respond to Ca(2+) addition in a manner similar to that which occurs when N-ethylmaleimide is present. Subsequent addition of mercaptoethanol produces an immediate increase in both DeltaE and -59DeltapH. At the same time Ca(2+) is rapidly accumulated by the organelles. 5. The above data are interpreted as indicating that under the conditions of Ca(2+) efflux seen here, the mitochondria retain their functional integrity. This contrasts with the uncoupling effect of Ca(2+) seen in the presence of P(i), which generally leads to a loss of mitochondrial integrity. We suggest that a unique mechanism of Ca(2+) cycling is able to take place when mitochondria have been treated with N-ethylmaleimide.

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Section: Discussioncontrasting

confidence: 47%

Section: Resultsmentioning

confidence: 90%

Calcium ion cycling in rat liver mitochondria

Ramachandran

Bygrave

1978

Biochemical Journal

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“…Its function can be inhibited by some small molecules, such as ruthenium red and RU360. Recently, the composition of the mitochondrial calcium uniporter was identified [16,17,18,19]. MICU1 is encoded by Micu1 , which is the first identified subunit.…”

Section: The Molecular Components and Calcium Transporting Mechanimentioning

confidence: 99%

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

Liao

Dong

Cheng

2017

IJMS

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The mitochondrial calcium uniporter (MCU)—a calcium uniporter on the inner membrane of mitochondria—controls the mitochondrial calcium uptake in normal and abnormal situations. Mitochondrial calcium is essential for the production of adenosine triphosphate (ATP); however, excessive calcium will induce mitochondrial dysfunction. Calcium homeostasis disruption and mitochondrial dysfunction is observed in many neurodegenerative disorders. However, the role and regulatory mechanism of the MCU in the development of these diseases are obscure. In this review, we summarize the role of the MCU in controlling oxidative stress-elevated mitochondrial calcium and its function in neurodegenerative disorders. Inhibition of the MCU signaling pathway might be a new target for the treatment of neurodegenerative disorders.

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“…RR is a well‐known and widely studied tool for modulation of mitochondrial calcium uptake. The uniporter is a gated ion channel and can be completely inhibited by micromolar concentrations of RR 18–24. RR can prevent mitochondrial calcium uptake in isolated mitochondria, cell culture, tissue culture, and in vivo 22, 24–27.…”

mentioning

confidence: 99%

“…The uniporter is a gated ion channel and can be completely inhibited by micromolar concentrations of RR 18–24. RR can prevent mitochondrial calcium uptake in isolated mitochondria, cell culture, tissue culture, and in vivo 22, 24–27. We have previously demonstrated that prevention of mitochondrial calcium uptake using RR prevents apoptosis in cultured HepG2 cells during the early rewarming period following an ischemic insult 28.…”

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confidence: 99%

Modulation of mitochondrial calcium management attenuates hepatic warm ischemia-reperfusion injury

et al. 2005

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Hepatic warm ischemia and reperfusion (IR) injury occurs in many clinical situations and has an important link to subsequent hepatic failure. The pathogenesis of this injury involves numerous pathways, including mitochondrial-associated apoptosis. We studied the effect of mitochondrial calcium uptake inhibition on hepatic IR injury using the specific mitochondrial calcium uptake inhibitor, ruthenium red (RR). Rats were subjected to 1 hour of 70% warm hepatic ischemia following RR pretreatment or vehicle injection. Sham-operated animals served as controls. Analysis was performed at 15 minutes, 1 hour, 3 hours, or 6 hours after reperfusion. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations were determined. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was performed to assess apoptosis, and hepatocellular necrosis was semiquantitated from hematoxylin and eosin -stained tissue sections. RR pretreatment significantly decreased both AST and ALT serum levels after 6 hours of reperfusion (AST: 1,556 ؎ 181 U/L vs. 597 ؎ 121 U/L, P ‫؍‬ 0.005; ALT: 1,118 ؎ 187 U/L vs. 294 ؎ 39 U/L, P ‫؍‬ 0.005). Apoptosis was observed within 15 minutes of reperfusion in vehicle-pretreated animals and peaked after 3 hours of reperfusion (98 ؎ 21 cells/high-power field [hpf]). Apoptosis was inhibited at all time points by RR pretreatment. Histologic evidence of necrosis was not observed prior to 3 hours of reperfusion (23% ؎ 4%), and maximal necrosis was observed after 6 hours of reperfusion (26% ؎ 1% percent area). RR pretreatment significantly decreased the necrotic percent area at both the 3-hour and the 6-hour time points (4.2% ؎ 2%; 3.7% ؎ 1%, respectively). Hepatic IR injury resulted in both apoptotic and necrotic cell death, which were attenuated by RR pretreatment. In conclusion, these observations implicate mitochondrial calcium uptake in the pathogenesis of hepatic IR injury. H epatic warm ischemia and reperfusion (IR) injury occur in many clinical situations including transplantation, resection, trauma, shock, hemorrhage, and thermal injury. Evidence exists linking the periods of ischemia associated with these events to subsequent liver failure. 1 In addition, there is evidence that the duration of the ischemic periods during hepatic resection directly correlates with postoperative liver dysfunction. [2][3][4][5] The pathogenesis of ischemic hepatocellular injury is complex and involves numerous mediators. [6][7][8][9] Although many authors have demonstrated apoptosis following hepatic ischemia, the role of mitochondrialassociated apoptotic mechanisms in hepatic IR injury remains unclear. A better understanding of the cellular pathophysiology of IR and identification of methods to attenuate this injury has important clinical implications.Within the last decade, a series of findings have shown that mitochondria play a central role in intracellular calcium dynamics. 10,11 Mitochondria can take up calcium rapidly via the ruthenium red...

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The inhibition of calcium uptake and release by rat liver mitochondria by ruthenium red

Cited by 29 publications

References 11 publications

Calcium ion cycling in rat liver mitochondria

Calcium ion cycling in rat liver mitochondria

The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

Modulation of mitochondrial calcium management attenuates hepatic warm ischemia-reperfusion injury

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