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Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.

Published version
Peer-reviewed

Repository DOI


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Authors

Moschandrea, Chrysanthi 
Evangelakos, Ioannis  ORCID logo  https://orcid.org/0000-0001-7328-6319
Herholz, Marija 
Schneider, Farina 

Abstract

Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes, which shows that the accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed an impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in intestinal epithelial cells. DARS2 deficiency caused a distinct lack of mature chylomicrons concomitant with a progressive dispersal of the Golgi apparatus in proximal enterocytes. This finding suggests that mitochondrial dysfunction results in impaired trafficking of chylomicrons from the endoplasmic reticulum to the Golgi, which in turn leads to storage of dietary lipids in large cytoplasmic LDs. Taken together, these results reveal a role for mitochondria in dietary lipid transport in enterocytes, which might be relevant for understanding the intestinal defects observed in patients with mitochondrial disorders5.

Description

Keywords

Animals, Mice, Aspartate-tRNA Ligase, Chylomicrons, Dietary Fats, Electron Transport Complex II, Endoplasmic Reticulum, Enterocytes, Epithelial Cells, Golgi Apparatus, Intestines, Lipid Droplets, Lipid Metabolism, Mitochondria

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

625

Publisher

Springer Science and Business Media LLC