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Mitochondria & Dietary Fat

iStock-1488349563Results of an experimental animal study clarifying the role of mitochondria in the processing and transport of dietary lipids were recently published in Nature. The gastrointestinal consequences of impaired mitochondrial function are not well understood, and this study was done to shed light on the specific role played by mitochondria in lipid processing, potentially leading to more targeted human interventions.

Breeding of mice lacking the DARS2 gene, specifically in intestinal epithelial cells (IECs, the cells primarily responsible for nutrient absorption), produced animals that lacked mitochondrial respiratory complexes and could not survive beyond 4 weeks. The DARS2 gene codes for mitochondrial aspartyl-tRNA synthetase 2, an enzyme critical to the synthesis of multiple mitochondrial proteins, with a deficit causing substantial mitochondrial dysfunction. The IECs accumulated lipids into large droplets, determined to be of a dietary origin, with additional evidence indicating that the transport of dietary lipids was impaired in these mice. Proteomic and metabolomic analyses were also performed, indicating a downregulation of lipid biosynthesis as well as a decrease in chylomicron production.

Further experiments included more specific changes, targeting specific units involved in oxidative phosphorylation for deletion, including SDHA (mitochondrial complex II) or COX10 (complex IV), again only in IECs. Both deletions resulted in the accumulation of large lipid droplets without some of the broader deficits observed in DARS2 knock-out mice.

These and additional experiments suggest that mitochondria play a key role in either chylomicron formation or the movement of chylomicrons from the endoplasmic reticulum to the plasma membrane. Mitochondrial dysfunction within IECs thus leads to the accumulation of lipids within these cells. As noted above, the GI impact of mitochondrial dysfunction in humans is not well recognized, though symptoms are a frequent consequence, and may include low appetite, vomiting, constipation, and diarrhea.

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