Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium

Stuart Smith, Andrzej Witkowski, Ayesha Moghul, Yuko Yoshinaga, Michael Nefedov, Pieter de Jong, Dejiang Feng, Loren Fong, Yiping Tu, Yan Hu, Stephen G. Young, Thomas Pham, Carling Cheung, Shana M. Katzman, Martin D. Brand, Casey L. Quinlan, Marcel Fens, Frans Kuypers, Stephanie Misquitta, Stephen M GriffeySon Tran, Afshin Gharib, Jens Knudsen, Hans Kristian Hannibal-Bach, Grace Wang, Sandra Larkin, Jennifer Thweatt, Saloni Pasta

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

A mouse model with compromised mitochondrial fatty acid synthesis has been engineered in order to assess the role of this pathway in mitochondrial function and overall health. Reduction in the expression of mitochondrial malonyl CoA-acyl carrier protein transacylase, a key enzyme in the pathway encoded by the nuclear Mcat gene, was achieved to varying extents in all examined tissues employing tamoxifen-inducible Cre-lox technology. Although affected mice consumed more food than control animals, they failed to gain weight, were less physically active, suffered from loss of white adipose tissue, reduced muscle strength, kyphosis, alopecia, hypothermia and shortened lifespan. The Mcat-deficient phenotype is attributed primarily to reduced synthesis, in several tissues, of the octanoyl precursors required for the posttranslational lipoylation of pyruvate and α-ketoglutarate dehydrogenase complexes, resulting in diminished capacity of the citric acid cycle and disruption of energy metabolism. The presence of an alternative lipoylation pathway that utilizes exogenous free lipoate appears restricted to liver and alone is insufficient for preservation of normal energy metabolism. Thus, de novo synthesis of precursors for the protein lipoylation pathway plays a vital role in maintenance of mitochondrial function and overall vigor.

Original languageEnglish (US)
Article numbere47196
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 15 2012

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Smith, S., Witkowski, A., Moghul, A., Yoshinaga, Y., Nefedov, M., de Jong, P., Feng, D., Fong, L., Tu, Y., Hu, Y., Young, S. G., Pham, T., Cheung, C., Katzman, S. M., Brand, M. D., Quinlan, C. L., Fens, M., Kuypers, F., Misquitta, S., ... Pasta, S. (2012). Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium. PLoS One, 7(10), [e47196]. https://doi.org/10.1371/journal.pone.0047196