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Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced.
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We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. 9 McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.Ĭells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM).8 Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA.7 GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.6 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA.5 Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA.4 Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA.3 Seahorse Bioscience, 16 Esquire Road, North Billerica, Massachusetts 01862, USA.2 Department of Radiology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.1 Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390-8502, USA.