Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction |
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Authors: | Giuseppe Cannino Riyad El-Khoury Marja Pirinen Bettina Hutz Pierre Rustin Howard T Jacobs Eric Dufour |
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Institution: | From the ‡Institute of Biomedical Technology and Centre for Laboratory Medicine, Tampere University Hospital, University of Tampere, 33014 Tampere, Finland and ;§INSERM U676 and Université Paris 7, Faculté de Médecine Denis Diderot, 75019 Paris, France |
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Abstract: | Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an “emergency shutdown” system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases. |
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Keywords: | Glucose Mitochondrial Diseases Respiratory Chain Signaling Bioenergetics/Electron Transfer Complex Cell Metabolism |
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