Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Charles P Najt; Santosh Adhikari; Timothy D Heden; Wenqi Cui; Erica R Gansemer; Adam J Rauckhorst; Todd W Markowski; LeeAnn Higgins; Evan W Kerr; Matthew D Boyum; Jonas Alvarez; Sophia Brunko; Dushyant Mehra; Elias M Puchner; Eric B Taylor; Douglas G Mashek

doi:10.1016/j.celrep.2023.112435

Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Cell Rep. 2023 May 30;42(5):112435. doi: 10.1016/j.celrep.2023.112435. Epub 2023 Apr 26.

Authors

Charles P Najt¹, Santosh Adhikari², Timothy D Heden¹, Wenqi Cui¹, Erica R Gansemer¹, Adam J Rauckhorst³, Todd W Markowski¹, LeeAnn Higgins¹, Evan W Kerr¹, Matthew D Boyum¹, Jonas Alvarez¹, Sophia Brunko¹, Dushyant Mehra², Elias M Puchner², Eric B Taylor⁴, Douglas G Mashek⁵

Affiliations

¹ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
² School of Physics and Astronomy, University of Minnesota, Minneapolis, MN, USA.
³ Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁴ Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA.
⁵ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA. Electronic address: dmashek@umn.edu.

Abstract

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.

Keywords: CP: Metabolism; MAM; cytosolic mitochondria; fatty acids; lipid anabolism; lipid catabolism; lipid droplets; organelle interactions; peridroplet mitochondria; perilipin 5; single-molecule localization microscopy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Fatty Acids* / metabolism
Lipid Droplets / metabolism
Lipid Metabolism*
Liver / metabolism
Proteome / metabolism

Substances

Fatty Acids
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding