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Small‐Molecule Targeting of the Mitochondrial Compartment with an Endogenously Cleaved Reversible Tag
Author(s) -
Ripcke Jens,
Zarse Kim,
Ristow Michael,
Birringer Marc
Publication year - 2009
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200900159
Subject(s) - lipoic acid , moiety , chemistry , mitochondrion , cytotoxicity , biochemistry , small molecule , compartment (ship) , aldehyde dehydrogenase , oxidative stress , reactive oxygen species , enzyme , stereochemistry , antioxidant , in vitro , oceanography , geology
Reversible mitochondrial shuttle : A novel concept in mitochondrial pharmacology allows the transport of bioactive compounds into the mitochondrial compartment and their subsequent release. A lipoic acid derivative containing a cleavable (“reversible”) triphenylphosphonium tag is endogenously cleaved by the mitochondrial aldehyde dehydrogenase (ALDH‐2) after mitochondrial accumulation.Targeted accumulation of chemically unaltered compounds within the mitochondrial compartment has not yet been achieved. Here we describe a reversible tag that is endogenously cleaved after mitochondrial accumulation has occurred. Specifically, we have reversibly tagged α ‐lipoic acid with a triphenylphosphonium moiety that is cleaved by the physiologically contained mitochondrial aldehyde dehydrogenase (ALDH‐2). This reversibly tagged compound activates the lipoic acidsensitive pyruvate dehydrogenase complex, and this results in increased glucose oxidation. We observed a reduction in ROS accumulation after preincubation with the reversibly tagged compound, whereas untagged or irreversibly tagged compounds either had no effect on ROS formation or rather caused increased oxidative stress, respectively. Lastly, the cytotoxicity of the reversibly tagged compound is less than that of the irreversibly tagged compound. Overall, reversible tagging combines decreased tag‐related cytotoxicity with increased bioactivity, and this potentially provides a novel concept in mitochondrial pharmacology.