Uncoupling of oxidative phosphorylation by curcumin: implication of its cellular mechanism of action.
Curcumin is a phytochemical isolated from the rhizome of turmeric. Recent reports have shown curcumin to have antioxidant, anti-inflammatory and anti-tumor properties as well as affecting the 5'-AMP activated protein kinase (AMPK), mTOR and STAT-3 signaling pathways. We provide evidence that curcumin acts as an uncoupler. Well-established biochemical techniques were performed on isolated rat liver mitochondria in measuring oxygen consumption, F(0)F(1)-ATPase activity and ATP biosynthesis. Curcumin displays all the characteristics typical of classical uncouplers like fccP and 2,4-dinitrophenol. In addition, at concentrations higher than 50 microM, curcumin was found to inhibit mitochondrial respiration which is a characteristic feature of inhibitory uncouplers. As a protonophoric uncoupler and as an activator of F(0)F(1)-ATPase, curcumin causes a decrease in ATP biosynthesis in rat liver mitochondria. The resulting change in ATP:AMP could disrupt the phosphorylation status of the cell; this provides a possible mechanism for its activation of AMPK and its downstream mTOR and STAT-3 signaling.
Lim
Han Wern
HW
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore.
Lim
Hwee Ying
HY
Wong
Kim Ping
KP
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000293:Adolescent; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014475:Uncoupling Agents / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000975:Antioxidants; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases; D003474:Curcumin