Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes
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Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes. / Moschandrea, Chrysanthi; Kondylis, Vangelis; Evangelakos, Ioannis; Herholz, Marija; Schneider, Farina; Schmidt, Christina; Yang, Ming; Ehret, Sandra; Heine, Markus; Jaeckstein, Michelle Y; Szczepanowska, Karolina; Schwarzer, Robin; Baumann, Linda; Bock, Theresa; Nikitopoulou, Efterpi; Brodesser, Susanne; Krüger, Marcus; Frezza, Christian; Heeren, Joerg; Trifunovic, Aleksandra; Pasparakis, Manolis.
in: NATURE, Jahrgang 625, Nr. 7994, 11.01.2024, S. 385-392.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes
AU - Moschandrea, Chrysanthi
AU - Kondylis, Vangelis
AU - Evangelakos, Ioannis
AU - Herholz, Marija
AU - Schneider, Farina
AU - Schmidt, Christina
AU - Yang, Ming
AU - Ehret, Sandra
AU - Heine, Markus
AU - Jaeckstein, Michelle Y
AU - Szczepanowska, Karolina
AU - Schwarzer, Robin
AU - Baumann, Linda
AU - Bock, Theresa
AU - Nikitopoulou, Efterpi
AU - Brodesser, Susanne
AU - Krüger, Marcus
AU - Frezza, Christian
AU - Heeren, Joerg
AU - Trifunovic, Aleksandra
AU - Pasparakis, Manolis
N1 - © 2023. The Author(s).
PY - 2024/1/11
Y1 - 2024/1/11
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Aspartate-tRNA Ligase/metabolism
KW - Chylomicrons/metabolism
KW - Dietary Fats/metabolism
KW - Electron Transport Complex II/metabolism
KW - Endoplasmic Reticulum/metabolism
KW - Enterocytes/metabolism
KW - Epithelial Cells/metabolism
KW - Golgi Apparatus/metabolism
KW - Intestines
KW - Lipid Droplets/metabolism
KW - Lipid Metabolism
KW - Mitochondria/metabolism
U2 - 10.1038/s41586-023-06857-0
DO - 10.1038/s41586-023-06857-0
M3 - SCORING: Journal article
C2 - 38123683
VL - 625
SP - 385
EP - 392
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7994
ER -