Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

• 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
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112435

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.