Editors' ChoiceCell Biology

ER-Derived ROS and Mitochondrial Dysfunction

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Sci. Signal.  27 Aug 2013:
Vol. 6, Issue 290, pp. ec200
DOI: 10.1126/scisignal.2004665

Enzymes in various subcellular compartments produce reactive oxygen species (ROS), such as superoxide, that cause oxidative damage to cellular components and act as signaling molecules. Mitochondrial dysfunction is associated with increased ROS production that may contribute to cellular aging and disease states. It has been widely assumed that the malfunctioning mitochondria themselves are the source of this increased ROS (see commentary by Murphy), but Leadsham et al. report that the endoplasmic reticulum (ER) is the major source of ROS in yeast with mitochondrial dysfunction. Aging and neurodegenerative disease are associated with decreased function of the mitochondrial electron transport chain enzyme cytochrome c oxidase (Cox), and the authors found that reduction or loss of Cox (Δcox4) indeed increased ROS accumulation in Saccharomyces cerevisiae undergoing diauxic shift. The diauxic shift occurs when cells switch from fermentative to oxidative metabolism in response to changes in carbon source availability and is characterized by increased mitochondrial respiration and biogenesis. Whereas the active form of the small guanosine triphosphatase Ras was distributed throughout the cytoplasm during diauxic shift in wild-type cells, active Ras accumulated at the outer mitochondrial membrane in Δcox4 cells and in cells in which the mitochondrial membrane potential was disrupted by ionophore treatment. ROS did not accumulate in Δcox4Δras2 cells during diauxic shift. The ER-localized NADPH oxidase Yno1 was also required for maximal ROS accumulation in Δcox4 cells. In wild-type cells, fluorescently tagged Yno1 localized to the ER before diauxic shift and was not detected after diauxic shift. Yno1 remained at the ER after diauxic shift in Δcox4 cells but disappeared from the ER in Δcox4Δras2 cells. Yno1 also accumulated at the ER after diauxic shift in cells that were unable to undergo ER-associated degradation (ERAD), suggesting that Yno1 is a target of ERAD. These results imply a model in which mitochondrial dysfunction stimulates Ras signaling that suppresses ERAD through an unknown mechanism, ultimately resulting in the ER accumulation of an enzyme (NADPH oxidase) that generates ROS.

J. E. Leadsham, G. Sanders, S. Giannaki, E. L. Bastow, R. Hutton, W. R. Naeimi, M. Breitenbach, C. W. Gourlay, Loss of cytochrome c oxidase promotes RAS-dependent ROS production from the ER resident NADPH oxidase, Yno1p, in yeast. Cell Metab. 18, 279–286 (2013). [PubMed]

M. P. Murphy, Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab. 18, 145–146 (2013). [PubMed]