Genetic defects in peroxisome morphogenesis (Pex11β, dynamin‐like protein 1, and nucleoside diphosphate kinase 3) affect docosahexaenoic acid‐phospholipid metabolism

Abstract

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 Drp1and 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.

Effects of phosphorylation on Drp1 activation by its receptors, actin, and cardiolipin

“…There is evidence that another NDPK, NME3 enriches on peroxisomes and mitochondria, and might work with Drp1 in a similar manner ( Honsho et al. , 2020 ; Abe et al. , 2023 ).…”

Precision Medicines for Retinal Lipid Metabolism-Related Pathologies

“…Peroxisomes are organelles found in all eukaryotic cells and are involved in processes such as α and β-oxidation of lipids, glyoxylate detoxification, amino acid degradation, and metabolism of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [29]. They are also important for the synthesis of plasmalogen, docosahexaenoic acid (DHA), and bile acid [30]. Lipid metabolism and ROS metabolism are both interconnected, and they require the cooperation of peroxisomes with other structures, such as mitochondria, endoplasmic reticulum (RE), lipid droplets, and lysosomes.…”

Convergent and divergent mechanisms of peroxisomal and mitochondrial division

“…Human patients with genetic defects in the components of the common division machinery, such as DRP1 (also called DLP1) or nucleoside diphosphate kinase 3 (NME3, mammalian homolog of DYNAMO1; Honsho et al, 2020 ) affecting peroxisomal division, are also affected in mitochondrial morphology and abundance ( Abe et al, 2023 ). NME3 localizes to both POs and mitochondria and generates GTP required for DRP1 activity.…”

“…Many excellent reviews exist on mitochondrial and/or PO dynamics, as well as the division machinery and its role in disease states ( Abe et al, 2023 ; Carmichael and Schrader, 2022 ; Chan, 2020 ; Mahalingam et al, 2021 ). This review seeks to highlight both the convergent and divergent aspects of the division of these organelles and the physiological processes that they are coupled to, within the overall cellular context.…”