Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet...

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Published in:	Cell reports (Cambridge) Vol. 42; no. 5; p. 112435
Main Authors:	Najt, Charles P., Adhikari, Santosh, Heden, Timothy D., Cui, Wenqi, Gansemer, Erica R., Rauckhorst, Adam J., Markowski, Todd W., Higgins, LeeAnn, Kerr, Evan W., Boyum, Matthew D., Alvarez, Jonas, Brunko, Sophia, Mehra, Dushyant, Puchner, Elias M., Taylor, Eric B., Mashek, Douglas G.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 30-05-2023 Elsevier
Subjects:	CP: Metabolism cytosolic mitochondria fatty acids Fatty Acids - metabolism lipid anabolism lipid catabolism lipid droplets Lipid Droplets - metabolism Lipid Metabolism Liver - metabolism MAM organelle interactions peridroplet mitochondria perilipin 5 Proteome - metabolism single-molecule localization microscopy fatty acids organelle interactions peridroplet mitochondria CP: Metabolism cytosolic mitochondria lipid anabolism perilipin 5 MAM lipid droplets lipid catabolism single-molecule localization microscopy
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Summary:	Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet mitochondria (PDM) and cytosolic mitochondria (CM) reveals that CM are enriched in proteins comprising various oxidative metabolism pathways, whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirms that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete medium. Additionally, mitochondrion-associated membranes (MAM) around PDM and CM differ in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways, whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity. [Display omitted] •CM are enriched in oxidative proteins and utilize FAs during fasting•PDM are enriched in lipid anabolism proteins and facilitate FA esterification•MAM around PDM and CM are unique and differentially regulate lipid metabolism•PLIN5 regulates the proteomes and functions of mitochondrial and MAM subpopulations Najt et al. reveal that the proteomes and functions of subpopulations of hepatic mitochondria and MAM differ based on their interactions with LDs. FAs are selectively trafficked to and oxidized in CM, especially during fasting, whereas PDM and associated MAM facilitate FA esterification and LD expansion.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS C.P.N., D.G.M., E.B.T., and E.M.P. conceived and designed the research. C.P.N., S.A., T.D.H., A.J.R., and T.W.M. performed experiments. C.P.N., S.A., S.B., T.D.H., A.J.R., E.R.G., L.H., M.D.B., J.A., E.M.P., and E.B.T. analyzed data. C.P.N., S.A., T.D.H., D.G.M., E.M.P., E.B.T., and A.J.R. interpreted results of experiments. C.P.N., S.A., and D.G.M. prepared figures. C.P.N. and D.G.M. drafted the manuscript. S.A., E.B.T., T.W.M., E.M.P., and A.J.R. contributed materials and reagents necessary for the completion of studies. C.P.N., D.G.M., E.B.T., E.R.G., and E.M.P. edited and revised the manuscript. All authors approved the final version of the manuscript.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2023.112435