Light control of mitochondrial complex I activity by a photoresponsive inhibitor

We recently developed a new class of inhibitors of bovine heart mitochondrial NADH-ubiquinone oxidoreductase (complex I), named Delta lac-acetogenin [Ichimaru et al. (2005) Biochemistry 44, 816-825]. The inhibitory potency of Delta lac-acetogenin is remarkably affected by the molecular shape of the alkyl side chains. We speculated that if the shape of the side chains can be changed by the trans-cis photoisomerization of the azobenzene unit that is introduced into the chain moiety, the inhibitory effect could be switched on and off in a reversible manner. Such a photoresponsive inhibitor may allow rapid, remote, and noninvasive control of complex I activity. Therefore, we here synthesized Delta lac-acetogenin ( 3) possessing an azobenzene unit in the side chains. H-1 NMR, HPLC, and UV-visible absorption analyses indicated that the azobenzene unit in 3 is rapidly and reversibly trans-cis isomerized by photoirradiation in chloroform and ethanol. The inhibitory effect of trans, trans-3 on complex I activity in submitochondrial particles was more potent than that of cis, cis-3. When 3 was applied at the nanomolar level to complex I, the inhibitory effect was reversibly reduced and enhanced by alternating irradiation by UV and visible light, respectively. The present study gives a positive clue to the light control of complex I activity.