ABSTRACT
Mitochondria: A Source of Reactive Oxygen Species .................................... 198 Lipid Peroxidation and Formation of 4-Hydroxy-2-Nonenal.......................... 199 Reactivity of 4-Hydroxy-2-Nonenal with Protein ........................................... 201 Inhibition of Mitochondrial Respiration by 4-Hydroxy-2-Nonenal ................ 202 Lipoic Acid as a Target of 4-Hydroxy-2-Nonenal Modification .................... 203 Detection of 4-Hydroxy-2-Nonenal-Modified Lipoic Acid............................. 205 Fate of Lipoic Acid 4-Hydroxy-2-Nonenal Conjugate.................................... 206 Reversible Oxidative Inhibition of a-Ketoglutarate Dehydrogenase .............. 207 Glutathionylation of a-Ketoglutarate Dehydrogenase..................................... 207 Glutathionylation of a-Ketoglutarate Dehydrogenase as an Antioxidant Response......................................................................... 209
Conclusion ....................................................................................................... 210 References ........................................................................................................ 210
In studies designed to establish molecular mechanisms by which free-radical species and derived products mediate mitochondrial dysfunction, lipoic acid presented itself as keenly susceptible to oxidative modification. Oxidative modification of this naturally occurring enzyme-bound cofactor results in profound deficits of specific enzymatic functions and, ultimately, deficits in oxidative
phosphorylation. In the following chapter, we will discuss molecular mechanisms by which different forms of oxidative stress irreversibly inactivate and reversibly inhibit the multienzyme complex a-ketoglutarate dehydrogenase (KGDH) by virtue of this enzyme’s reliance on the covalently attached lipoic acid for activity. A brief discussion of mitochondria as a source of oxygen derived free radicals and pro-oxidants and of oxidative modifications to macromolecules, particularly with respect to membrane lipids, is offered to provide relevance for these findings.
