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

29 Citations (Scopus)

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

Fingerprint

Lipoylation
Transgenic Mice
Fatty Acids
genetically modified organisms
Tissue
fatty acids
energy metabolism
Energy Metabolism
synthesis
mice
energy
malonyl coenzyme A
Hypothermia
Ketoglutarate Dehydrogenase Complex
Acyl Carrier Protein
Malonyl Coenzyme A
Pyruvate Dehydrogenase Complex
acyl carrier protein
tamoxifen
muscle strength

ASJC Scopus subject areas

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

Cite this

Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium. / Smith, Stuart; Witkowski, Andrzej; Moghul, Ayesha; Yoshinaga, Yuko; Nefedov, Michael; de Jong, Pieter; Feng, Dejiang; Fong, Loren; Tu, Yiping; Hu, Yan; Young, Stephen G.; Pham, Thomas; Cheung, Carling; Katzman, Shana M.; Brand, Martin D.; Quinlan, Casey L.; Fens, Marcel; Kuypers, Frans; Misquitta, Stephanie; Griffey, Stephen M; Tran, Son; Gharib, Afshin; Knudsen, Jens; Hannibal-Bach, Hans Kristian; Wang, Grace; Larkin, Sandra; Thweatt, Jennifer; Pasta, Saloni.

In: PLoS One, Vol. 7, No. 10, e47196, 15.10.2012.

Research output: Contribution to journalArticle

Smith, S, Witkowski, A, Moghul, A, Yoshinaga, Y, Nefedov, M, de Jong, P, Feng, D, Fong, L, Tu, Y, Hu, Y, Young, SG, Pham, T, Cheung, C, Katzman, SM, Brand, MD, Quinlan, CL, Fens, M, Kuypers, F, Misquitta, S, Griffey, SM, Tran, S, Gharib, A, Knudsen, J, Hannibal-Bach, HK, Wang, G, Larkin, S, Thweatt, J & Pasta, S 2012, 'Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium', PLoS One, vol. 7, no. 10, e47196. https://doi.org/10.1371/journal.pone.0047196
Smith, Stuart ; Witkowski, Andrzej ; Moghul, Ayesha ; Yoshinaga, Yuko ; Nefedov, Michael ; de Jong, Pieter ; Feng, Dejiang ; Fong, Loren ; Tu, Yiping ; Hu, Yan ; Young, Stephen G. ; Pham, Thomas ; Cheung, Carling ; Katzman, Shana M. ; Brand, Martin D. ; Quinlan, Casey L. ; Fens, Marcel ; Kuypers, Frans ; Misquitta, Stephanie ; Griffey, Stephen M ; Tran, Son ; Gharib, Afshin ; Knudsen, Jens ; Hannibal-Bach, Hans Kristian ; Wang, Grace ; Larkin, Sandra ; Thweatt, Jennifer ; Pasta, Saloni. / Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium. In: PLoS One. 2012 ; Vol. 7, No. 10.
@article{7536febc9e6f462790c2ab18d029b9d8,
title = "Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium",
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.",
author = "Stuart Smith and Andrzej Witkowski and Ayesha Moghul and Yuko Yoshinaga and Michael Nefedov and {de Jong}, Pieter and Dejiang Feng and Loren Fong and Yiping Tu and Yan Hu and Young, {Stephen G.} and Thomas Pham and Carling Cheung and Katzman, {Shana M.} and Brand, {Martin D.} and Quinlan, {Casey L.} and Marcel Fens and Frans Kuypers and Stephanie Misquitta and Griffey, {Stephen M} and Son Tran and Afshin Gharib and Jens Knudsen and Hannibal-Bach, {Hans Kristian} and Grace Wang and Sandra Larkin and Jennifer Thweatt and Saloni Pasta",
year = "2012",
month = "10",
day = "15",
doi = "10.1371/journal.pone.0047196",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Compromised Mitochondrial Fatty Acid Synthesis in Transgenic Mice Results in Defective Protein Lipoylation and Energy Disequilibrium

AU - Smith, Stuart

AU - Witkowski, Andrzej

AU - Moghul, Ayesha

AU - Yoshinaga, Yuko

AU - Nefedov, Michael

AU - de Jong, Pieter

AU - Feng, Dejiang

AU - Fong, Loren

AU - Tu, Yiping

AU - Hu, Yan

AU - Young, Stephen G.

AU - Pham, Thomas

AU - Cheung, Carling

AU - Katzman, Shana M.

AU - Brand, Martin D.

AU - Quinlan, Casey L.

AU - Fens, Marcel

AU - Kuypers, Frans

AU - Misquitta, Stephanie

AU - Griffey, Stephen M

AU - Tran, Son

AU - Gharib, Afshin

AU - Knudsen, Jens

AU - Hannibal-Bach, Hans Kristian

AU - Wang, Grace

AU - Larkin, Sandra

AU - Thweatt, Jennifer

AU - Pasta, Saloni

PY - 2012/10/15

Y1 - 2012/10/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867497045&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867497045&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0047196

DO - 10.1371/journal.pone.0047196

M3 - Article

C2 - 23077570

AN - SCOPUS:84867497045

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e47196

ER -