Regulation of Mitochondrial reactive Oxygen species by Succinate

P9 REGULATION OF MITOCHONDRIAL REACTIVE OXYGEN SPECIES BY SUCCINATE Michael Murphy, Medical Research Council Mitochondrial Biology Unit, UK Mitochondrial Reactive O[ygen Species (ROS) have long been known to contribute to damage in conditions such as ischaemia-reperfusion (IR) injury in heart attack. More recently they have also been implicated in redo[ signalling. Over the past few years we have developed a mitochondria-targeted S-nitrosating agent, called MitoSNO, that we showed was effective in preventing ROS formation in IR injury with therapeutic implications. In addition, the protection by this compound suggested that ROS production in IR injury was mainly coming from comple[ I. This led us to investigate the mechanism of the ROS production and using a metabolomic approach we found that the ROS production in IR injury came from the accumulation of succinate during ischaemia that then drove mitochondrial ROS production by reverse electron transport at comple[ I during reperfusion. This surprising mechanism led up to develop further new therapeutic approaches to impact on the damage that mitochondrial ROS do in pathology and also to e[plore how mitochondrial ROS can act as redo[ signals. I will discuss how these une[pected mechanisms may lead to redo[ signals from mitochondria in conditions such as cancer.

Michael Murphy

XXXXXX doi: 10.1016/j.freeradbiomed.2015.10.011

P10 SIRTUINS IN STRESS RESPONSE Marcia Haigis, Harvard Medical School, USA A hallmark feature of tumor cells is a shift in fuel metabolism to support cell growth and enhance stress response pathways. We have investigated the role of mitochondrial posttranslation modi¿cation in tumor metabolism, as many mitochondrial enzymes are modi¿ed by acetylation and acylation. Mitochondrial sirtuins are NAD-dependent enzymes that bind and regulate metabolic and stress pathways within the mitochondria. We have discovered that SIRT3, a mitochondrial deacetylase, represses cellular glycolysis through the regulation of HIFα, a transcription factor that increases gene e[pression of glycolytic targets. SIRT, a less studied mitochondrial sirtuin is an integral part of the metabolic stress response. Thus, a better understanding of sirtuin-mediated regulation may identify novel ways to therapeutically target diseases associated with aging, such as cancer.

Marcia Haigis

XXXXXX doi: 10.1016/j.freeradbiomed.2015.10.012

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