1Laboratoire d’Informatique de l’Ecole Polytechnique-Unité Mixte de Recherche 7161, Ecole Polytechnique, Palaiseau 91128, France
2Assistance Publique des Hôpitaux de Paris, 149 avenue Victoria, 75004, Paris, France
3LRI, Université Paris-Sud, CNRS, Université Paris-Saclay, 91405, Orsay, France
4MaIAGE, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
Large literature studies on eukaryotic cell metabolism forced to conceptualize mitochondria as the energy powerhouse of the cell. That came from its evolutionary origin and also because it is the main source of ATP, the energy currency of cells. However, recent studies and ours tend to consider mitochondria “more than just a powerhouse”, otherwise, a central organelle of the cell with large spectrum of applications for biochemical reaction modulations and biomolecules productions1–3. Recent studies reported that mitochondria network is continuously remodeled by fusion and fission events according to the metabolic context4. Thus, mitochondrial activity plays pivotal role on energetic yield and/or efficiency, especially when submitted to variable carbon concentrations. Fermentation and oxidative phosphorylation are two intertwined metabolic pathways usually considered to characterize mitochondrial efficiency. Indeed, when a molecule of glucose is converted to pyruvate through glycolysis, it yields 2 ATP molecules. Then, pyruvate can be converted to carbon dioxide and 36 ATP molecules by oxidative phosphorylation (OxPhos). Alternatively, pyruvate can also be catabolized to ethanol by backer’s yeast or to lactate in muscle cells by fermentation. In this sense, ATP yield of fermentation is much lower compared to OxPhos. Respiration to fermentation transitions occurs in optional aerobe organisms upon oxygen limitation (Pasteur effect), high rate of glycolysis (Crabtree effect) and even in cancer cells (Warburg effect)5. All these mechanisms are assimilated to the global overflow metabolism. In our last studies we aimed to decipher mitochondria efficiency in Yarrowia lipolytica, an obligate aerobe yeast known to produce large amount of citrate and with high capacity for intracellular lipids accumulation. Using genome- scale metabolic model of Y. lipolytica, we first characterized overflow metabolism in this oleaginous yeast and then we identified mitochondrial levers to trigger citrate overproduction. The model predicts that inhibition the alternative oxidase (AOX), a protein responsible for Y. lipolytica respiration during stationary phase, allows citrate optimization. These results were experimentally confirmed (prepared for submission to Nature metabolism).
- da Veiga Moreira, et al. Cell cycle progression is regulated by intertwined redox oscillators. Theor. Biol. Med. Model. 12, 10 (2015).
- da Veiga Moreira, et al. The Redox Status of Cancer Cells Supports Mechanisms behind the Warburg Effect.Metabolites 6, (2016).
- da Veiga Moreira, J. da V. et al. Metabolic therapies inhibit tumor growth in vivo and in silico. Rep. 9, 3153 (2019).
- Mitra, K., Wunder, C., Roysam, B., Lin, G. & Lippincott-Schwartz, J. A hyperfused mitochondrial state achieved at G1–S regulates cyclin E buildup and entry into S phase. Natl. Acad. Sci. 106, 11960–11965 (2009).
- Overflow Metabolism – 1st Edition. (2018). Available at https://www.elsevier.com/books/overflow- metabolism/vazquez/978-0-12-812208-2. (Accessed: 18th October 2018)