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The Endoplasmic Reticulum Enzyme DGAT2 Is Found in Mitochondria-associated Membranes and Has a Mitochondrial Targeting Signal That Promotes Its Association with Mitochondria
Open accessAbstract
The synthesis and storage of neutral lipids in lipid droplets is a fundamental property of eukaryotic cells, but the spatial organization of this process is poorly understood. Here we examined the intracellular localization of acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), an enzyme that catalyzes the final step of triacylglycerol (TG) synthesis in eukaryotes. We found that DGAT2 expressed in cultured cells localizes to the endoplasmic reticulum (ER) under basal conditions. After providing oleate to drive TG synthesis, DGAT2 also localized to near the surface of lipid droplets, where it co-localized with mitochondria. Biochemical fractionation revealed that DGAT2 is present in mitochondria-associated membranes, specialized domains of the ER that are highly enriched in lipid synthetic enzymes and interact tightly with mitochondria. The interaction of DGAT2 with mitochondria depended on 67 N-terminal amino acids of DGAT2, which are not conserved in family members that have different catalytic functions. This targeting signal was sufficient to localize a red fluorescent protein to mitochondria. A highly conserved, positively charged, putative mitochondrial targeting signal was identified in murine DGAT2 between amino acids 61 and 66. Thus, DGAT2, an ER-resident transmembrane domain-containing enzyme, is also found in mitochondria-associated membranes, where its N terminus may promote its association with mitochondria.
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“DGAT2 is localized around LDs where it is required for TG synthesis51,52,53.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [53]
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Metadata
- Authors
- Stone, S. J., Levin, M. C., Zhou, P., Han, J., Walther, T. C., & Farese, R. V.
- Affiliations
- University of Saskatchewan (CA)
- Gladstone Institutes (US)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Farese, Robert V.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 284
- Issue
- 8
- Pages
- 5352-5361
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2643492
- OpenAlex
- W2054600904
- Cited by
- 390
- References
- 55
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 26 · 2023: 34 · 2022: 20 · 2021: 21 · 2020: 33 · 2019: 15 · 2018: 20 · 2017: 30 · 2016: 18 · 2015: 15 · 2014: 15 · 2013: 26 · 2012: 27
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- National Cancer Institute (CO6 RR018928)
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01-DK065599, R01DK065599)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- DGAT2, mitochondria-associated membranes, mitochondrial targeting signal, endoplasmic reticulum, lipid droplets, triglyceride synthesis, neutral lipid storage, protein localization, N-terminal targeting sequence, oleate
- MeSH terms
- Animals, Chlorocebus aethiops, Endoplasmic Reticulum, Humans, Mitochondria, Triglycerides, COS Cells, Protein Transport, Protein Sorting Signals, Mitochondrial Proteins, Diacylglycerol O-Acyltransferase, Mitochondrial Membranes, Mice
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