Dinitrophenol-induced mitochondrial uncoupling in vivo triggers respiratory adaptation in HepG2 cells.
Here, we show that 3 days of mitochondrial uncoupling, induced by low concentrations of dinitrophenol (10 and 50 microM) in cultured human HepG2 cells, triggers cellular metabolic adaptation towards oxidative metabolism. Chronic respiratory uncoupling of HepG2 cells induced an increase in cellular oxygen consumption, oxidative capacity and cytochrome c oxidase activity. This was associated with an upregulation of COXIV and ANT3 gene expression, two nuclear genes that encode mitochondrial proteins involved in oxidative phosphorylation. Glucose consumption, lactate and pyruvate production and growth rate were unaffected, indicating that metabolic adaptation of HepG2 cells undergoing chronic respiratory uncoupling allows continuous and efficient mitochondrial ATP production without the need to increase glycolytic activity. In contrast, 3 days of dinitrophenol treatment did not change the oxidative capacity of human 143B.TK(-) cells, but it increased glucose consumption, lactate and pyruvate production. Despite a large increase in glycolytic metabolism, the growth rate of 143B.TK(-) cells was significantly reduced by dinitrophenol-induced mitochondrial uncoupling. We propose that chronic respiratory uncoupling may constitute an internal bioenergetic signal, which would initiate a coordinated increase in nuclear respiratory gene expression, which ultimately drives mitochondrial metabolic adaptation within cells.
Desquiret
Valérie
V
Department of Biochemistry and Molecular Biology, INSERM UMR-694, 4 rue Larrey, F-49033 Angers cedex, France.
Loiseau
Dominique
D
Jacques
Caroline
C
Douay
Olivier
O
Malthièry
Yves
Y
Ritz
Patrick
P
Roussel
Damien
D
D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D000222:Adaptation, Physiological / Q000187:drug effects; D033781:Adenine Nucleotide Translocator 3 / Q000235:genetics*; D019069:Cell Respiration / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000235:genetics*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D010085:Oxidative Phosphorylation / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*; D015854:Up-Regulation
D033781:Adenine Nucleotide Translocator 3; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D014475:Uncoupling Agents; D019344:Lactic Acid; D019289:Pyruvic Acid; D003576:Electron Transport Complex IV; D005947:Glucose; D019297:2,4-Dinitrophenol