Light Control of Mitochondrial Complex I Activity by a Photoresponsive Inhibitor

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Abstract
We recently developed a new class of inhibitors of bovine heart mitochondrial NADH−ubiquinone oxidoreductase (complex I), named Δlac-acetogenin [Ichimaru et al. (2005) Biochemistry 44, 816−825]. The inhibitory potency of Δlac-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 Δlac-acetogenin (3) possessing an azobenzene unit in the side chains. 1H 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.

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