Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes

Chrysanthi Moschandrea, Vangelis Kondylis, Ioannis Evangelakos, Marija Herholz, Farina Schneider, Christina Schmidt, Ming Yang, Sandra Ehret, Markus Heine, Michelle Y. Jaeckstein, Karolina Szczepanowska, Robin Schwarzer, Linda Baumann, Theresa Bock, Efterpi Nikitopoulou, Susanne Brodesser, Marcus Krüger, Christian Frezza, Joerg Heeren, Aleksandra Trifunovic () and Manolis Pasparakis ()
Additional contact information
Chrysanthi Moschandrea: University of Cologne
Vangelis Kondylis: University of Cologne
Ioannis Evangelakos: University Medical Center Hamburg-Eppendorf
Marija Herholz: University of Cologne
Farina Schneider: University of Cologne
Christina Schmidt: University of Cologne
Ming Yang: University of Cologne
Sandra Ehret: University Medical Center Hamburg-Eppendorf
Markus Heine: University Medical Center Hamburg-Eppendorf
Michelle Y. Jaeckstein: University Medical Center Hamburg-Eppendorf
Karolina Szczepanowska: University of Cologne
Robin Schwarzer: University of Cologne
Linda Baumann: University of Cologne
Theresa Bock: University of Cologne
Efterpi Nikitopoulou: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Susanne Brodesser: University of Cologne
Marcus Krüger: University of Cologne
Christian Frezza: University of Cologne
Joerg Heeren: University Medical Center Hamburg-Eppendorf
Aleksandra Trifunovic: University of Cologne
Manolis Pasparakis: University of Cologne

Nature, 2024, vol. 625, issue 7994, 385-392

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06857-0

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