Mitochondrial Oxygen Consumption Is Synergistically Inhibited by Metallothionein and Calcium

Simpkins, Cuthbert O.; Balderman, Samuel C.; Mensah, Eugene

doi:10.1006/jsre.1998.5383

Cited by 26 publications

(17 citation statements)

References 18 publications

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“…zinc ion was thought to be only in the nanomolar or picomolar range (40)(41)(42). The demonstration that MT inhibits respiration (7,8), the observation that this inhibition occurs at micromolar concentrations of Zn 7 -MT, and studies on the zinc transfer potential of MT (10) now point to a mechanism by which MT transports zinc into mitochondria to exert the above described effects. Together with the observed T-mediated activation of zinc-inhibited respiration, these findings recognize and demonstrate that MT and T modulate mitochondrial respiration in a zinc-dependent manner.…”

Section: Discussionmentioning

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).…”

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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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Zinc metallothionein imported into liver mitochondria modulates respiration

Maret²,

Vallée³

2001

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

237

170

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“…[46] MT has also been proven to inhibit oxygen consumption of intact mitochondria. [47] MT-null mice (with MT-1 and -2 genes disrupted) develop a mild form of obesity. [48] The incubation of mitochondria with physiological, (micromolar) concentrations of MT results in the import of MT into the mitochondria (the lysines of MT have been postulated to be important in this transportation).…”

Section: Mt and Respirationmentioning

confidence: 99%

The Metallothionein/Thionein System: An Oxidoreductive Metabolic Zinc Link

2008

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Metallothioneins (MTs) were discovered more than 50 years ago and identified as low‐molecular weight, sulfhydryl‐rich proteins that were subsequently found to bind zinc predominantly. The binding of seemingly redox inactive zinc ions allows MT to play a central role in oxidoreductive cellular metabolism, cellular zinc distribution and homeostasis. In this interpretive study, we discuss the interaction of MT with physiologically relevant molecules and its effect on zincthiolate bonds. These interactions are linked to recent progress in the functional role of MT in cellular zinc transport, energy production, and protection of the organism against oxidative stress and neurodegenerative diseases.

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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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Mitochondrial Oxygen Consumption Is Synergistically Inhibited by Metallothionein and Calcium

Cited by 26 publications

References 18 publications

Zinc metallothionein imported into liver mitochondria modulates respiration

Zinc metallothionein imported into liver mitochondria modulates respiration

The Metallothionein/Thionein System: An Oxidoreductive Metabolic Zinc Link

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

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