Voltage-dependent Anion Channels Control the Release of the Superoxide Anion from Mitochondria to Cytosol*

By Derick Han, F. Antunes, R. Canali, D. Rettori, E. Cadenas. Journal of Biological Chemistry, 2003

701 citations recorded by the source corpus.

Several reactions in biological systems contribute to maintain the steady-state concentrations of superoxide anion (O 2 ⨪ ) and hydrogen peroxide (H2O2). The electron transfer chain of mitochondria is a well documented source of H2O2; however, the release of O 2 ⨪ from mitochondria into cytosol has not been unequivocally established. This study was aimed at validating mitochondria as sources of cytosolic O 2 ⨪ , elucidating the mechanisms underlying the release of O 2 ⨪ from mitochondria into cytosol, and assessing the role of outer membrane voltage-dependent anion channels (VDACs) in this process. Isolated rat heart mitochondria supplemented with complex I or II substrates generate an EPR signal ascribed to O 2 ⨪ . Inhibition of the signal in a concentration-dependent manner by both manganese-superoxide dismutase and cytochromec proteins that cannot cross the mitochondrial membrane supports the extramitochondrial location of the spin adduct. Basal rates of O 2 ⨪ release from mitochondria were estimated at ∼0.04 nmol/min/mg protein, a value increased ∼8-fold by the complex III inhibitor, antimycin A. These estimates, obtained by quantitative spin-trapping EPR, were confirmed by fluorescence techniques, mainly hydroethidine oxidation and horseradish peroxidase-basedp-hydroxyphylacetate dimerization. Inhibitors of VDAC, 4′-diisothiocyano-2,2′-disulfonic acid stilbene (DIDS), and dextran sulfate (in a voltage-dependent manner) inhibited O 2 ⨪ production from mitochondria by ∼55%, thus suggesting that a large portion of O 2 ⨪ exited mitochondria via these channels. These findings are discussed in terms of competitive decay pathways for O 2 ⨪ in the intermembrane space and cytosol as well as the implications of these processes for modulating cell signaling pathways in these compartments.

Subfields: Aerospace Engineering, Sociology and Political Science, Transportation

View Paper: https://www.semanticscholar.org/paper/2ce1ca20ebae4ffadc15d191a5ca4ae2c34c9e6e

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Citations in the corpus

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• Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis (2014, positive): “Mitochondrial complex III also generates superoxide into the mitochondrial intermembrane space where it escapes through VDACs to cytosol and is converted into H2O2 by SOD1 (Han et al., 2003; Muller et al., 2004).”
• Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling (2013, positive): “Of note, complex III emits superoxide into both the matrix and the intermembrane space; intermembrane-space superoxide can access the cytosol through voltage-dependent anion channels without prior conversion to H2O2 (Han et al., 2003; Muller et al., 2004; Murphy, 2009).”
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• How mitochondria produce reactive oxygen species (2008, background): “…dyes such as hydroethidine and MitoSOX TM [47–50], measurement of the reaction of O 2 •− with compounds to form chemiluminescent products [44,51], spin trapping [52] or measurement of the inactivation rate of aconitase [53] do provide useful information on mitochondrial O 2 •− production.”
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• Riding the DUBway: regulation of protein trafficking by deubiquitylating enzymes (2006, positive): “Redox factor-1, for instance, translocates from a diffuse cytosolic location into the nucleus with oxidative stress to facilitate the DNA-binding activity of NF-κB (Angkeow et al., 2002).”
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