1. Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells
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Mariantonietta Capristo, Marcella Attimonelli, Mariano Francesco Caratozzolo, Maria Antonietta Calvaruso, Pier Luigi Lollini, Apollonia Tullo, Anna Ghelli, Flaviana Marzano, Valerio Carelli, Giordano Nicoletti, Romana Fato, Claudia Calabrese, Caterina Manzari, Carla De Giovanni, Valentina Giorgio, Anna Maria Porcelli, Claudio Ceccarelli, Ivana Kurelac, Giuseppe Gasparre, Christine M. Betts, Patrizia Nanni, Michela Rugolo, Christian Bergamini, Luisa Iommarini, Giovanni Romeo, Calabrese C., Iommarini L., Kurelac I., Calvaruso M.A., Capristo M., Lollini P.L., Nanni P., Bergamini C., Nicoletti G., De Giovanni C., Ghelli A., Giorgio V., Caratozzolo M.F., Marzano F., Manzari C., Betts C.M., Carelli V., Ceccarelli C., Attimonelli M., Romeo G., Fato R., Rugolo M., Tullo A., Gasparre G., and Porcelli A.M.
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Mutation ,Research ,mtDNA mutation ,HIF-1α ,HYPOXIA ,Mitochondrion ,Biology ,Bioinformatics ,medicine.disease_cause ,Warburg effect ,Allotopic expression ,Cell biology ,Psychiatry and Mental health ,MITOCHONDRIA ,Tumor progression ,Anaerobic glycolysis ,Cancer cell ,medicine ,Glycolysis ,COMPLEX I ,Cancer - Abstract
Background Aerobic glycolysis, namely the Warburg effect, is the main hallmark of cancer cells. Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift. This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression, some of which rely on functional mitochondria. In this framework, the role of mitochondrial complex I is still debated, in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism. The aim of this work is to provide the proof of concept that functional complex I is necessary to sustain tumor progression. Methods Complex I-null osteosarcoma cells were complemented with allotopically expressed complex I subunit 1 (MT-ND1). Complex I re-assembly and function recovery, also in terms of NADH consumption, were assessed. Clones were tested for their ability to grow in soft agar and to generate tumor masses in nude mice. Hypoxia levels were evaluated via pimonidazole staining and hypoxia-inducible factor-1α (HIF-1α) immunoblotting and histochemical staining. 454-pyrosequencing was implemented to obtain global transcriptomic profiling of allotopic and non-allotopic xenografts. Results Complementation of a truncative mutation in the gene encoding MT-ND1, showed that a functional enzyme was required to perform the glycolytic shift during the hypoxia response and to induce a Warburg profile in vitro and in vivo, fostering cancer progression. Such trigger was mediated by HIF-1α, whose stabilization was regulated after recovery of the balance between α-ketoglutarate and succinate due to a recuperation of NADH consumption that followed complex I rescue. Conclusion Respiratory complex I is essential for the induction of Warburg effect and adaptation to hypoxia of cancer cells, allowing them to sustain tumor growth. Differently from other mitochondrial tumor suppressor genes, therefore, a complex I severe mutation such as the one here reported may confer anti-tumorigenic properties, highlighting the prognostic values of such genetic markers in cancer.
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