Dataset Information

Mitochondria regulate dietary lipid processing in enterocytes

ABSTRACT: Digested dietary fats are taken up, processed and transported by enterocytes to supply the body with lipids. Most absorbed lipids are assembled into pre-chylomicrons in the endoplasmic reticulum (ER) of enterocytes, which are then transported to the Golgi for maturation and subsequent secretion to the circulation. The role of mitochondria in regulating intestinal lipid transport remains unknown. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with intestinal epithelial cell (IEC)-specific ablation of the mitochondrial-specific aspartyl - tRNA synthetase DARS2, as well as of the respiratory chain subunit SDHA or the assembly factor COX10 failed to thrive and showed massive accumulation of lipids within large lipid droplets (LDs) in enterocytes of the proximal small intestine (SI). Feeding a fat-free diet inhibited the formation of LDs in DARS2-deficient enterocytes, showing that accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in IECs. Moreover, DARS2-deficient enterocytes showed a distinct lack of mature chylomicrons concomitant with a disorganisation of the Golgi apparatus, suggesting that impaired ER to Golgi trafficking underlies impaired chylomicron production and secretion. Taken together, these results revealed a vital role of mitochondria in regulating dietary lipid transport in enterocytes, which is relevant for understanding the intestinal and nutritional defects observed in patients with mitochondrial defects.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Intestine, Intestinal Epithelial Cell

SUBMITTER: Theresa Bock

LAB HEAD: Manolis Pasparakis

PROVIDER: PXD026934 | Pride | 2023-12-21

REPOSITORIES: Pride

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			Action	DRS
	20210324_E1_LC6col188_TB_Chrysanthi_intestinal_cells_843.raw	Raw
	20210324_E1_LC6col188_TB_Chrysanthi_intestinal_cells_844.raw	Raw
	20210324_E1_LC6col188_TB_Chrysanthi_intestinal_cells_845.raw	Raw
	20210324_E1_LC6col188_TB_Chrysanthi_intestinal_cells_846.raw	Raw
	20210324_E1_LC6col188_TB_Chrysanthi_intestinal_cells_847.raw	Raw

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Publications

Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.

Moschandrea Chrysanthi C Kondylis Vangelis V Evangelakos Ioannis I Herholz Marija M Schneider Farina F Schmidt Christina C Yang Ming M Ehret Sandra S Heine Markus M Jaeckstein Michelle Y MY Szczepanowska Karolina K Schwarzer Robin R Baumann Linda L Bock Theresa T Nikitopoulou Efterpi E Brodesser Susanne S Krüger Marcus M Frezza Christian C Heeren Joerg J Trifunovic Aleksandra A Pasparakis Manolis M

Nature 20231220 7994

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 circulation<sup>1</sup>. 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 aspa ...[more]

PMID: 38123683

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Project description:Understanding how dietary nutrients alter lipid metabolism in the host is important in deciphering the physiological mechanisms that regulate organismal health. Using the nematode Caenorhabditis elegans as a model organism, I found that a novel gram-positive monomethyl branched-chain fatty acid (mmBCFA) rich bacteria, Microbacterium sp., isolated from C. elegans natural habit can induce supersized lipid droplets (LDs) up to 30 μm in diameter in older animals and adversely affect their lifespan, development rate and brood size. Lipidomic analysis indicated that Microbacterium sp.-fed worms primarily accumulate dietary mmBCFAs in the triacylglycerides stored within LDs. Transcriptomic analysis discovered that the mmBCFA-rich bacteria diet would enhance fatty acid desaturase fat-7 expression and therefore polyunsaturated fatty acids (PUFAs) production to support LD biosynthesis and fusion processes. Additionally, the diet from Microbacterium sp. significantly inhibits creatine kinase argk-1, which results in the suppression of the AMP-activated protein kinase pathway, leading to a halt in mitochondrial beta-oxidation, enhanced lipid de novo synthesis and activation of a mitochondrial unfolded protein response (UPRmt) in C. elegans. Furthermore, using this enlarged LD-inducing bacteria diet, a gain-of-function missense mutation in scav-4 is identified to exacerbate the LD expansion phenotype while the loss of scav-4 results in diminished lipid storage in the worms. Lipidomic analysis showed that the L462F missense mutation nearly doubles the uptake of dietary mmBCFAs, whereas deletion mutants exhibit a reduced proportion of dietary mmBCFAs in total lipids. The localization of SCAV-4 on the intestinal apical membrane and its phylogenetic similarity to the human CD36 fatty acid transporter suggest that SCAV-4 is a homolog of CD36. Structural analysis indicates that the missense mutation is likely located within the transport tunnel, potentially affecting lipid transport. Among the six SCAV family members in C. elegans, SCAV-6 appears to be a less critical paralog compared to SCAV-4, sharing similar expression patterns and showing reduced lipid storage upon deletion. Notably, the transcriptomic analysis reveals that the SCAV-4 missense mutation does not cause much transcriptomic changes under the E. coli OP50 diet but affects over 3,000 genes in response to the Microbacterium sp. diet, suggesting that animals with SCAV-4(L462F) mutation is much more sensitive to the mmBCFAs-rich diet than the wild-type animals. This finding highlights the influence of host genetic variations in the interactions with dietary nutrients, which has strong impact on host metabolism.