Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1.
OBJECTIVE
Glucocorticoids, such as dexamethasone, enhance hepatic energy metabolism and gluconeogenesis partly through changes in mitochondrial function. Mitochondrial function is influenced by the balance between mitochondrial fusion and fission events. However, whether glucocorticoids modulate mitochondrial function through the regulation of mitochondrial dynamics is currently unknown.


RESULTS
Here, we report that the effects of dexamethasone on mitochondrial function and gluconeogenesis in hepatoma cells are dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Dexamethasone increased routine oxygen consumption, maximal respiratory capacity, superoxide anion, proton leak, and gluconeogenesis in hepatoma cells. Under these conditions, dexamethasone altered mitochondrial morphology, which was paralleled by a large increase in Drp1 expression, and reduced mitofusin 1 (Mfn1) and Mfn2. In vivo dexamethasone treatment also enhanced Drp1 expression in mouse liver. On the basis of these observations, we analyzed the dependence on the Drp1 function of dexamethasone effects on mitochondrial respiration and gluconeogenesis. We show that the increase in mitochondrial respiration and gluconeogenesis induced by dexamethasone are hampered by the inhibition of Drp1 function.


METHODS
Our findings provide the first evidence that the effects of glucocorticoids on hepatic metabolism require the mitochondrial fission protein Drp1.


CONCLUSIONS
In summary, we demonstrate that the mitochondrial effects of dexamethasone both on mitochondrial respiration and on the gluconeogenic pathway depend on Drp1.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
María Isabel
MI
Hernández-Alvarez
José C
JC
Paz
David
D
Sebastián
Juan Pablo
JP
Muñoz
Marc
M
Liesa
Jessica
J
Segalés
Manuel
M
Palacín
Antonio
A
Zorzano
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D034281:Dynamins / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008928:Mitochondria; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D005938:Glucocorticoids; D013481:Superoxides; D003907:Dexamethasone; D006861:Hydrogen Peroxide; C519851:Dnm1l protein, rat; D034281:Dynamins