TY - JOUR
T1 - Genetic defects in peroxisome morphogenesis (Pex11β, dynamin-like protein 1, and nucleoside diphosphate kinase 3) affect docosahexaenoic acid-phospholipid metabolism
AU - Abe, Yuichi
AU - Wanders, Ronald J. A.
AU - Waterham, Hans R.
AU - Mandel, Hanna
AU - Falik-Zaccai, Tzipora C.
AU - Ishihara, Naotada
AU - Fujiki, Yukio
N1 - Funding Information: JSPS Grants‐in‐Aid for Scientific Research, Grant/Award Numbers: JP17H03675, JP15K21743, JP15K14511, JP26116007, JP19K07386; the Takeda Science Foundation; the Naito Foundation, Japan; the Novartis Foundation (Japan) for the Promotion of Science Funding information Funding Information: We thank the other members of our laboratory for helpful discussions. This work was supported in part by JSPS Grants‐in‐Aid for Scientific Research Grant Numbers JP19K07386 (to Y.A.) and JP26116007, JP15K14511, JP15K21743, and JP17H03675 (to Y.F.); grants (to Y.F.) from the Takeda Science Foundation, the Naito Foundation, Japan, and the Novartis Foundation (Japan) for the Promotion of Science. Funding Information: We thank the other members of our laboratory for helpful discussions. This work was supported in part by JSPS Grants-in-Aid for Scientific Research Grant Numbers JP19K07386 (to Y.A.) and JP26116007, JP15K14511, JP15K21743, and JP17H03675 (to Y.F.); grants (to Y.F.) from the Takeda Science Foundation, the Naito Foundation, Japan, and the Novartis Foundation (Japan) for the Promotion of Science. Publisher Copyright: © 2022 SSIEM.
PY - 2023/3
Y1 - 2023/3
N2 - Peroxisomes are essential organelles involved in lipid metabolisms including plasmalogen biosynthesis and β-oxidation of very long-chain fatty acids. Peroxisomes proliferate by the growth and division of pre-existing peroxisomes. The peroxisomal membrane is elongated by Pex11β and then divided by the dynamin-like GTPase, DLP1 (also known as DRP1 encoded by DNM1L gene), which also functions as a fission factor for mitochondria. Nucleoside diphosphate kinase 3 (NME3) localized in both peroxisomes and mitochondria generates GTP for DLP1 activity. Deficiencies of either of these factors induce abnormal morphology of peroxisomes and/or mitochondria, and are associated with central nervous system dysfunction. To investigate whether the impaired division of peroxisomes affects lipid metabolisms, we assessed the phospholipid composition of cells lacking each of the different division factors. In fibroblasts from the patients deficient in DLP1, NME3, or Pex11β, docosahexaenoic acid (DHA, C22:6)-containing phospholipids were found to be decreased. Conversely, the levels of several fatty acids such as arachidonic acid (AA, C20:4) and oleic acid (C18:1) were elevated. Mouse embryonic fibroblasts from Drp1- and Pex11β-knockout mice also showed a decrease in the levels of phospholipids containing DHA and AA. Collectively, these results suggest that the dynamics of organelle morphology exert marked effects on the fatty acid composition of phospholipids.
AB - Peroxisomes are essential organelles involved in lipid metabolisms including plasmalogen biosynthesis and β-oxidation of very long-chain fatty acids. Peroxisomes proliferate by the growth and division of pre-existing peroxisomes. The peroxisomal membrane is elongated by Pex11β and then divided by the dynamin-like GTPase, DLP1 (also known as DRP1 encoded by DNM1L gene), which also functions as a fission factor for mitochondria. Nucleoside diphosphate kinase 3 (NME3) localized in both peroxisomes and mitochondria generates GTP for DLP1 activity. Deficiencies of either of these factors induce abnormal morphology of peroxisomes and/or mitochondria, and are associated with central nervous system dysfunction. To investigate whether the impaired division of peroxisomes affects lipid metabolisms, we assessed the phospholipid composition of cells lacking each of the different division factors. In fibroblasts from the patients deficient in DLP1, NME3, or Pex11β, docosahexaenoic acid (DHA, C22:6)-containing phospholipids were found to be decreased. Conversely, the levels of several fatty acids such as arachidonic acid (AA, C20:4) and oleic acid (C18:1) were elevated. Mouse embryonic fibroblasts from Drp1- and Pex11β-knockout mice also showed a decrease in the levels of phospholipids containing DHA and AA. Collectively, these results suggest that the dynamics of organelle morphology exert marked effects on the fatty acid composition of phospholipids.
KW - Pex11β
KW - dynamin-like protein 1
KW - impaired peroxisome division
KW - lipidomics
KW - nucleoside diphosphate kinase 3 (NME3)
KW - polyunsaturated fatty acid
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85145060238&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36522796
UR - http://www.scopus.com/inward/record.url?scp=85145060238&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12582
DO - https://doi.org/10.1002/jimd.12582
M3 - Article
C2 - 36522796
SN - 0141-8955
VL - 46
SP - 273
EP - 285
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 2
ER -