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
Affiliations
Charles P. Najt
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Santosh Adhikari
School of Physics and Astronomy, University of Minnesota, Minneapolis, MN, USA
Timothy D. Heden
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Wenqi Cui
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Erica R. Gansemer
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Adam J. Rauckhorst
Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Todd W. Markowski
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
LeeAnn Higgins
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Evan W. Kerr
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Matthew D. Boyum
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Jonas Alvarez
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Sophia Brunko
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
Dushyant Mehra
School of Physics and Astronomy, University of Minnesota, Minneapolis, MN, USA
Elias M. Puchner
School of Physics and Astronomy, University of Minnesota, Minneapolis, MN, USA
Eric B. Taylor
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
Douglas G. Mashek
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; Corresponding author
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.
