Effect of metallothionein I on mitochondrial oxygen consumption

Simpkins, Cuthbert O.; Hao-Liao, Zhao; Torrence, Cynthia A.

doi:10.1016/0024-3205(94)00883-3

Cited by 14 publications

(13 citation statements)

References 11 publications

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“…† In the absence of ADP, incubation of mitochondria with zinc activates oxygen consumption (data not shown; ref. 7). Apparently, incubation allows enough time for zinc to reach mitochondrial sites where it can affect the rate of succinate oxidation.…”

Section: The Effects Of Mt Mt-domain Peptides and Zinc On Respirationmentioning

confidence: 99%

“…Addition of zinc to isolated mitochondria inhibits respiration, an effect that has been traced to multiple sites in the electron transport chain (9). Simpkins et al (7) compared the inhibitory effects of MT and zinc and concluded that the effect of zinc alone occurs at concentrations higher by orders of magnitude than those thought to be available based on the known MT-zinc binding constant. They conjectured that the MT effect should not be attributed to its bound metals.…”

mentioning

confidence: 99%

“…So far, metallothionein (MT) is the only protein that has been implicated in cellular zinc distribution (6). We became interested in the function of MT in relation to mitochondria because commercial preparations of cadmium-containing MT have previously been shown to inhibit oxygen consumption of intact mitochondria (7,8). Addition of zinc to isolated mitochondria inhibits respiration, an effect that has been traced to multiple sites in the electron transport chain (9).…”

mentioning

confidence: 99%

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Zinc metallothionein imported into liver mitochondria modulates respiration

Maret²,

Vallée³

2001

Proc. Natl. Acad. Sci. U.S.A.

237

170

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Metallothionein (MT) localizes in the intermembrane space of liver mitochondria as well as in the cytosol and nucleus. Incubation of intact liver mitochondria with physiological, micromolar concentrations of MT leads to the import of MT into the mitochondria where it inhibits respiration. This activity is caused by the Nterminal ␤-domain of MT; in this system, the isolated C-terminal ␣-domain is inactive. Free zinc inhibits respiration at concentrations commensurate with the zinc content of either MT or the isolated ␤-domain, indicating that MT inhibition involves zinc delivery to mitochondria. Respiratory inhibition of uncoupled mitochondria identifies the electron transfer chain as the primary site of inhibition. The apoform of MT, thionein, is an endogenous chelating agent and activates zinc-inhibited respiration with a 1:1 stoichiometry ([zinc binding sites]͞[zinc]). Carbamoylation of the lysines of MT significantly attenuates the inhibitory effect, suggesting that these residues are critical for the passage of MT through the outer mitochondrial membrane. Such an import pathway has been proposed for other proteins that also lack a mitochondrial targeting sequence, e.g., apocytochrome c, and possibly Cox17, a mitochondrial copper chaperone that is the only protein known so far to exhibit significant primary sequence homology to MT. The presence and respiratory inhibition of MT in liver, but not heart, mitochondria suggest a hitherto unknown biological modulating activity of MT in cellular respiration and energy metabolism in a tissue-specific manner. Z inc has a multitude of known cellular functions (1), but knowledge regarding its functions in mitochondria is still scant. Mitochondrial zinc constitutes a significant fraction of total cellular zinc. It has been estimated that in B cell-rich islets 32% of the total zinc is in mitochondria (2). The concentration of zinc in rat liver mitochondria is lower than that in the cytosol (3), indicating the existence of mechanisms to maintain this gradient and to regulate the amount of mitochondrial zinc, which seems to be quite variable. Thus, orally administered zinc salts increase zinc in rat liver mitochondria (4), and mitochondria of epithelial prostate cells are particularly rich in zinc (5), but its concentration remains lower than in the cytosol. Molecules that transport zinc to mitochondria and distribute it within them, as well as the control of these processes, remain to be identified and defined. So far, metallothionein (MT) is the only protein that has been implicated in cellular zinc distribution (6). We became interested in the function of MT in relation to mitochondria because commercial preparations of cadmium-containing MT have previously been shown to inhibit oxygen consumption of intact mitochondria (7,8). Addition of zinc to isolated mitochondria inhibits respiration, an effect that has been traced to multiple sites in the electron transport chain (9). Simpkins et al. (7) compared the inhibitory effects of MT and zinc and concluded that the effect o...

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Section: The Effects Of Mt Mt-domain Peptides and Zinc On Respirationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Zinc metallothionein imported into liver mitochondria modulates respiration

Maret²,

Vallée³

2001

Proc. Natl. Acad. Sci. U.S.A.

237

170

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“…About 80% of the accumulated cadmium in bivalves is sequestered by metallothioneins (Roesijadi, 1996;Giguere et al, 2003), which were previously believed to remove cadmium from the physiologically active pool. However, recent studies have shown that both free and metallothionein-bound cadmium ions have a potential to strongly affect mitochondrial function (Simpkins et al, 1994(Simpkins et al, , 1998. Therefore, both temperature and cadmium are potent modulators of mitochondrial function of oysters in nature.…”

mentioning

confidence: 99%

Cadmium effects on mitochondrial function are enhanced by elevated temperatures in a marine poikilotherm,Crassostrea virginicaGmelin(Bivalvia: Ostreidae)

Sokolova

2004

Journal of Experimental Biology

151

116

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SUMMARY Marine intertidal mollusks, such as oysters, are exposed to multiple stressors in estuaries, including varying environmental temperature and levels of trace metals, which may interactively affect their physiology. In order to understand the combined effects of cadmium and elevated temperature on mitochondrial bioenergetics of marine mollusks, respiration rates and mitochondrial volume changes were studied in response to different cadmium levels (0–1000 μmol l–1) and temperatures (15, 25 and 35°C) in isolated mitochondria from the eastern oyster Crassostrea virginica acclimated at 15°C. It was found that both cadmium and temperature significantly affect mitochondrial function in oysters. Elevated temperature had a rate-enhancing effect on state 3 (ADP-stimulated) and states 4 and 4+ (representative of proton leak) respiration, and the rate of temperature-dependent increase was higher for states 4 and 4+ than for state 3 respiration. Exposure of oyster mitochondria to 35°C resulted in a decreased respiratory control and phosphorylation efficiency (P/O ratio)compared to that of the acclimation temperature (15°C), while an intermediate temperature (25°C) had no effect. Cadmium exposure did not lead to a significant volume change in oyster mitochondria in vitro. Low levels of cadmium (1–5 μmol l–1) stimulated the rate of proton leak in oyster mitochondria, while not affecting ADP-stimulated state 3 respiration. In contrast, higher cadmium levels (10–50 μmol l–1) had little or no effect on proton leak, but significantly inhibited state 3 respiration by 40–80% of the control rates. Elevated temperature increased sensitivity of oyster mitochondria to cadmium leading to an early inhibition of ADP-stimulated respiration and an onset of complete mitochondrial uncoupling at progressively lower cadmium concentrations with increasing temperature. Enhancement of cadmium effects by elevated temperatures suggests that oyster populations subjected to elevated temperatures due to seasonal warming or global climate change may become more susceptible to trace metal pollution, and vice versa.

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“…membrane protein asymmetrically disposed on the outer surface, whereas cytochrome c is a soluble protein that associates through electrostatic interactions with the outer surface of the mitochondrial inner membrane. Considering that the outer membrane of the mitochondrion is capable of freely admitting molecules of molecular weight of up to 10 kDa [23], interactions between gadolinium, either as free ions or bound to proteins [8], and cytochromes c I and c may take place. In agreement with this proposal, eight ion-binding sites have been identi¢ed for gadolinium on the surface of cytochrome c, which exhibit di¡erent binding speci¢cities [24].…”

Section: Resultsmentioning

confidence: 99%

Effects of the Kupffer cell inactivator gadolinium chloride on rat liver oxygen uptake and content of mitochondrial cytochromes

1998

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The effect of gadolinium chloride (GdCl Q ) on the content of rat liver mitochondrial cytochromes was investigated in relation to the basal rate of O P uptake and Kupffer cell functioning, assessed in liver perfusion studies. (1) A single dose of GdCl Q (10 mg/kg) produced a significant diminution in Kupffer cell functioning, evidenced by the decreases in colloidal carbon uptake and in carbon-induced O P uptake observed at 62 4 h after treatment, without changes in the sinusoidal lactate dehydrogenase efflux as index of tissue viability; at 48 h after GdCl Q administration, carbon phagocytosis was recovered to control values, whereas carbon-induced O P uptake remained lower than control values. (2) GdCl Q also caused a 34% decrease in the basal rate of O P consumption of the liver at 24 h after treatment, which returned towards control values at 48 h. (3) The content of mitochondrial cytochromes c I and c at 24 h after GdCl Q treatment was significantly reduced by 40 and 32%, respectively, which returned to control values at 48 h, without changes in that of cytochromes b and a+a Q . It is concluded that GdCl Q -induced decrease in liver O P consumption is a reversible phenomenon that seems to be due to a diminution in the content of mitochondrial cytochromes c I and c.z 1998 Federation of European Biochemical Societies.

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Effect of metallothionein I on mitochondrial oxygen consumption

Cited by 14 publications

References 11 publications

Zinc metallothionein imported into liver mitochondria modulates respiration

Zinc metallothionein imported into liver mitochondria modulates respiration

Cadmium effects on mitochondrial function are enhanced by elevated temperatures in a marine poikilotherm,Crassostrea virginicaGmelin(Bivalvia: Ostreidae)

Effects of the Kupffer cell inactivator gadolinium chloride on rat liver oxygen uptake and content of mitochondrial cytochromes

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