Kinetics and control of oxidative phosphorylation in rat liver mitochondria after dexamethasone treatment.
The present investigation was undertaken in order to evaluate the contributions of ATP synthesis and proton leak reactions to the rate of active respiration of liver mitochondria, which is altered following dexamethasone treatment (1.5 mg/kg per day for 5 days). We applied top-down metabolic control analysis and its extension, elasticity analysis, to gain insight into the mechanisms of glucocorticoid regulation of mitochondrial bioenergetics. Liver mitochondria were isolated from dexamethasone-treated, pair-fed and control rats when in a fed or overnight fasted state. Injection of dexamethasone for 5 days resulted in an increase in the fraction of the proton cycle of phosphorylating liver mitochondria, which was associated with a decrease in the efficiency of the mitochondrial oxidative phosphorylation process in liver. This increase in proton leak activity occurred with little change in the mitochondrial membrane potential, despite a significant decrease in the rate of oxidative phosphorylation. Regulation analysis indicates that mitochondrial membrane potential homoeostasis is achieved by equal inhibition of the mitochondrial substrate oxidation and phosphorylation reactions in rats given dexamethasone. Our results also suggest that active liver mitochondria from dexamethasone-treated rats are capable of maintaining phosphorylation flux for cellular purposes, despite an increase in the energetic cost of mitochondrial ATP production due to increased basal proton permeability of the inner membrane. They also provide a complete description of the effects of dexamethasone treatment on liver mitochondrial bioenergetics.
Roussel
Damien
D
Laboratoire de Biochimie et Biologie Moléculaire, INSERM EMI-U 00.18, 4 rue Larrey, F-49033 Angers cedex, France.
Dumas
Jean-François
JF
Simard
Gilles
G
Malthièry
Yves
Y
Ritz
Patrick
P
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D004435:Eating / Q000502:physiology; D004526:Efficiency / Q000187:drug effects / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology*; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017494:Proton Pumps / Q000187:drug effects / Q000502:physiology; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley
D005230:Fatty Acids, Nonesterified; D017494:Proton Pumps; D011522:Protons; D003907:Dexamethasone; D000255:Adenosine Triphosphate