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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, Vol. 625, No. 7994, 11.01.2024, p. 385-392.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Moschandrea, C, Kondylis, V, Evangelakos, I, Herholz, M, Schneider, F, Schmidt, C, Yang, M, Ehret, S, Heine, M, Jaeckstein, MY, Szczepanowska, K, Schwarzer, R, Baumann, L, Bock, T, Nikitopoulou, E, Brodesser, S, Krüger, M, Frezza, C, Heeren, J, Trifunovic, A & Pasparakis, M 2024, 'Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes', NATURE, vol. 625, no. 7994, pp. 385-392. https://doi.org/10.1038/s41586-023-06857-0

APA

Moschandrea, C., Kondylis, V., Evangelakos, I., Herholz, M., Schneider, F., Schmidt, C., Yang, M., Ehret, S., Heine, M., Jaeckstein, M. Y., Szczepanowska, K., Schwarzer, R., Baumann, L., Bock, T., Nikitopoulou, E., Brodesser, S., Krüger, M., Frezza, C., Heeren, J., ... Pasparakis, M. (2024). Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes. NATURE, 625(7994), 385-392. https://doi.org/10.1038/s41586-023-06857-0

Vancouver

Moschandrea C, Kondylis V, Evangelakos I, Herholz M, Schneider F, Schmidt C et al. Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes. NATURE. 2024 Jan 11;625(7994):385-392. https://doi.org/10.1038/s41586-023-06857-0

Bibtex

@article{669099de67df45249e482e27aae60d5c,
title = "Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes",
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.",
keywords = "Animals, Mice, Aspartate-tRNA Ligase/metabolism, Chylomicrons/metabolism, Dietary Fats/metabolism, Electron Transport Complex II/metabolism, Endoplasmic Reticulum/metabolism, Enterocytes/metabolism, Epithelial Cells/metabolism, Golgi Apparatus/metabolism, Intestines, Lipid Droplets/metabolism, Lipid Metabolism, Mitochondria/metabolism",
author = "Chrysanthi Moschandrea and Vangelis Kondylis and Ioannis Evangelakos and Marija Herholz and Farina Schneider and Christina Schmidt and Ming Yang and Sandra Ehret and Markus Heine and Jaeckstein, {Michelle Y} and Karolina Szczepanowska and Robin Schwarzer and Linda Baumann and Theresa Bock and Efterpi Nikitopoulou and Susanne Brodesser and Marcus Kr{\"u}ger and Christian Frezza and Joerg Heeren and Aleksandra Trifunovic and Manolis Pasparakis",
note = "{\textcopyright} 2023. The Author(s).",
year = "2024",
month = jan,
day = "11",
doi = "10.1038/s41586-023-06857-0",
language = "English",
volume = "625",
pages = "385--392",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7994",

}

RIS

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 -