title: Glucose modulates respiratory complex I activity in response to acute mitochondrial dysfunction.
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.
authors.affiliation: Institute of Biomedical Technology and Centre for Laboratory Medicine, Tampere University Hospital, University of Tampere, 33014 Tampere, Finland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannino
authors.forename: Riyad
authors.initials: R
authors.lastname: El-Khoury
authors.forename: Marja
authors.initials: M
authors.lastname: Pirinen
authors.forename: Bettina
authors.initials: B
authors.lastname: Hutz
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Howard T
authors.initials: HT
authors.lastname: Jacobs
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
mesh_terms: D000818:Animals; D002938:Ciona intestinalis / Q000378:metabolism; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000378:metabolism; D010766:Phosphorylation; D010940:Plant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D000099188:Alternative Oxidase
chemical_list: D042967:Electron Transport Complex I; D005947:Glucose; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D029701:Saccharomyces cerevisiae Proteins; D000099188:Alternative Oxidase; C493237:Ndi1 protein, S cerevisiae