Membrane Potential-controlled Inhibition of Cytochromec Oxidase by Zinc

Mills, Denise A.; Schmidt, Bryan; Hiser, Carrie; Westley, Erica; Ferguson‐Miller, Shelagh

doi:10.1074/jbc.m111922200

Cited by 84 publications

(132 citation statements)

References 51 publications

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“…The specific activity in the absence of M 2ϩ , ϳ8 mol e Ϫ min Ϫ1 mg Ϫ1 , is equal to that of complex I in the inner mitochondrial membrane (30 in Group 12, is also effective. A similar trend was reported previously for modulation of the catalytic activity of cytochrome c oxidase by divalent cations (33). The concentration dependence of the Zn 2ϩ inhibition is described below.…”

Section: The Effect Of Divalent Cations On the Nadh:decylubiquinonesupporting

confidence: 79%

“…Similar modes of zinc inhibition have been observed in many other protontranslocating membrane proteins. Zn 2ϩ inhibits the bacterial photosynthetic reaction center by binding to amino acid residues that mediate proton transfer to Q B (51,52); it probably inhibits the cytochrome bc 1 complex by preventing proton egress from the Q O site (17,31), and it inhibits proton transfer in cytochrome c oxidase by binding at the entrance to one or more proton channels (18,32,33,35). In the future, zinc binding may be applied to localize proton channels or other key structural catalytic features in complex I in a similar fashion.…”

Section: Is Complex I Inhibition Relevant To Zn 2ϩmentioning

confidence: 99%

“…The aims of this work are thus 2-fold: first, to define the limits and possibilities for the role of complex I in zinc-mediated pathologies by determining the timescale and potency of zinc inhibition; and second, to define the molecular mechanism of zinc inhibition to further investigate the catalytic mechanism of complex I. In particular, zinc binding has proven valuable in localizing and elucidating the mechanisms of proton transfer in the cytochrome bc 1 complex (17, 31) and cytochrome c oxidase (18,19,(32)(33)(34)(35), whereas the mechanism of proton transfer in complex I remains undetermined.…”

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confidence: 99%

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The Inhibition of Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) by Zn2+

Sharpley

Hirst

2006

Journal of Biological Chemistry

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NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria is a highly complicated, membrane-bound enzyme. It is central to energy transduction, an important source of cellular reactive oxygen species, and its dysfunction is implicated in neurodegenerative and muscular diseases and in aging. Here, we describe the effects of Zn 2؉ on complex I to define whether complex I may contribute to mediating the pathological effects of zinc in states such as ischemia and to determine how Zn 2؉ can be used to probe the mechanism of complex I. Zn 2؉ inhibits complex I more strongly than Mg 2؉ , Ca 2؉ , Ba 2؉ , and Mn 2؉ to Cu 2؉ or Cd 2؉ . It does not inhibit NADH oxidation or intramolecular electron transfer, so it probably inhibits either proton transfer to bound quinone or proton translocation. Thus, zinc represents a new class of complex I inhibitor clearly distinct from the many ubiquinone site inhibitors. No evidence for increased superoxide production by zinc-inhibited complex I was detected. Zinc binding to complex I is mechanistically complicated. During catalysis, zinc binds slowly and progressively, but it binds rapidly and tightly to the resting state(s) of the enzyme. Reactivation of the inhibited enzyme upon the addition of EDTA is slow, and inhibition is only partially reversible. The IC 50 value for the Zn 2؉ inhibition of complex I is high (10 -50 M, depending on the enzyme state); therefore, complex I is unlikely to be a major site for zinc inhibition of the electron transport chain. However, the slow response of complex I to a change in Zn 2؉ concentration may enhance any physiological consequences.

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Section: The Effect Of Divalent Cations On the Nadh:decylubiquinonesupporting

confidence: 79%

Section: Is Complex I Inhibition Relevant To Zn 2ϩmentioning

confidence: 99%

mentioning

confidence: 99%

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The Inhibition of Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) by Zn2+

Sharpley

Hirst

2006

Journal of Biological Chemistry

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“…Results from earlier studies have shown that the activity of wild-type CytcO is inhibited by zinc ions (Zn 2+ ) (28)(29)(30)(31)(32)(33)(34)(35). One of the suggested Zn 2+ binding sites is located near Asp-132, consistent with structural data of the mitochondrial CytcO (36).…”

Section: Resultssupporting

confidence: 63%

“…Because proton uptake through the D pathway presumably is not rate limiting for this activity, any effects of Zn 2+ addition may reflect binding to other sites (32)(33)(34). We observed the same decrease in activity upon addition of Zn 2+ to the N139T/D132N as to the wildtype CytcO, which indicates that zinc binding to the other sites was not affected by the D pathway mutations.…”

Section: Resultssupporting

confidence: 52%

Role of aspartate 132 at the orifice of a proton pathway in cytochromecoxidase

Johansson

Högbom

Carlsson

et al. 2013

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

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Proton transfer across biological membranes underpins central processes in biological systems, such as energy conservation and transport of ions and molecules. In the membrane proteins involved in these processes, proton transfer takes place through specific pathways connecting the two sides of the membrane via control elements within the protein. It is commonly believed that acidic residues are required near the orifice of such proton pathways to facilitate proton uptake. In cytochrome c oxidase, one such pathway starts near a conserved Asp-132 residue. Results from earlier studies have shown that replacement of Asp-132 by, e.g., Asn, slows proton uptake by a factor of ∼5,000. Here, we show that proton uptake at full speed (∼10 4 s −1 ) can be restored in the Asp-132–Asn oxidase upon introduction of a second structural modification further inside the pathway (Asn-139–Thr) without compensating for the loss of the negative charge. This proton-uptake rate was insensitive to Zn 2+ addition, which in the wild-type cytochrome c oxidase slows the reaction, indicating that Asp-132 is required for Zn 2+ binding. Furthermore, in the absence of Asp-132 and with Thr at position 139, at high pH (>9), proton uptake was significantly accelerated. Thus, the data indicate that Asp-132 is not strictly required for maintaining rapid proton uptake. Furthermore, despite the rapid proton uptake in the Asn-139–Thr/Asp-132–Asn mutant cytochrome c oxidase, proton pumping was impaired, which indicates that the segment around these residues is functionally linked to pumping.

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Zinc: The brain's dark horse

Bitanihirwe

Cunningham

2009

Synapse

235

154

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Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.

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Membrane Potential-controlled Inhibition of Cytochromec Oxidase by Zinc

Cited by 84 publications

References 51 publications

The Inhibition of Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) by Zn2+

The Inhibition of Mitochondrial Complex I (NADH:Ubiquinone Oxidoreductase) by Zn2+

Role of aspartate 132 at the orifice of a proton pathway in cytochromecoxidase

Zinc: The brain's dark horse

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