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Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3

Lookup NU author(s): Professor Robert Taylor

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Abstract

The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERR alpha). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD(+)-dependent deacetylase and is critically dependent on NAD(+) levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies. (C) 2016 Elsevier Inc. All rights reserved.

Publication metadata

Author(s): Mathieu L, Costa AL, Le Bachelier C, Slama A, Lebre AS, Taylor RW, Bastin J, Djouadi F

Publication type: Article

Publication status: Published

Journal: Free Radical Biology and Medicine

Year: 2016

Volume: 96

Pages: 190-198

Print publication date: 01/07/2016

Online publication date: 25/04/2016

Acceptance date: 22/04/2016

Date deposited: 03/11/2016

ISSN (print): 0891-5849

ISSN (electronic): 1873-4596

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.027

DOI: 10.1016/j.freeradbiomed.2016.04.027

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