Hydroperoxy Fatty Acid Cycling Mediated by Mitochondrial Uncoupling Protein UCP2*

Functional activation of mitochondrial uncoupling protein-2 (UCP2) is proposed to decrease reactive oxygen species production. Skulachev and Goglia (Skulachev, V. P., and Goglia, F. (2003) FASEB J. 17, 1585–1591) hypothesized that hydroperoxy fatty acid anions are translocated by UCPs but cannot flip-flop across the membrane. We found that the second aspect is otherwise; the addition of synthesized linoleic acid hydroperoxides (LAOOH, a mix of four isomers) caused a fast flip-flop-dependent acidification of liposomes, comparable with the linoleic acid (LA)-dependent acidification. Using Escherichia coli-expressed UCP2 reconstituted into liposomes we found that LAOOH induced purine nucleotide-sensitive H+ uniport in UCP2-proteoliposomes with higher affinity than LA (Km values 97 μm for LAOOH and 275 μm for LA). In UCP2-proteoliposomes LAOOH also induced purine nucleotide-sensitive K+ influx balanced by anionic charge transfer, indicating that LAOOH was also transported as an anion with higher affinity than linoleate anion, the Km values being 90 and 350 μm, respectively. These data suggest that hydroperoxy fatty acids are transported via UCP2 by a fatty acid cycling mechanism. This may alternatively explain the observed activation of UCP2 by the externally generated superoxide. The ability of LAOOH to induce UCP2-mediated H+ uniport points to the essential role of superoxide reaction products, such as hydroperoxyl radical, hydroxyl radical, or peroxynitrite, initiating lipoperoxidation, the released products of which support the UCP2-mediated uncoupling and promote the feedback down-regulation of mitochondrial reactive oxygen species production.

• Publication year

  2004

• Venue

  Journal of Biological Chemistry

• Publication date

  2004-12-17

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M405339200PMID 15475368
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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