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; Lee Ann 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

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

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English (US)
Article number	112435
Journal	Cell reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112435
State	Published - May 30 2023

Bibliographical note

Funding Information:
We thank the University of Minnesota Imaging Center (Marker Sanders, Gail Celio, Guillermo Marques, and Thomas Pengo), the Center for Mass Spectrometry and Proteomics (Candace Guerrero), the Mayo Clinic Microscopy and Cell Analysis Core Facility (Trace Christensen and Jeffrey Salisbury), and the University of Iowa Metabolomics Core Facility for providing instrumentation and expertise. We thank Mahima Devarajan, Ann Hertzel, and David Berhnlor for scientific discussions and Margaret Harter for technical assistance. Funding was provided for C.N. ( NIH : T32AG029796 , K99AG070104 , AHA: 20POST35180115 ), T.D.H. ( NIH : K01DK125258 ), E.W.K. ( NIH : T32DK007203 ), E.B.T. ( NIH : R01DK104998 and University of Iowa Healthcare Distinguished Scholars Award), E.M.P. ( NIH : R21GM127965 ), and D.G.M. ( NIH : R01DK132849 and R01DK114401 and the University of Minnesota Institute on Diabetes and Obesity and the University of Iowa Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility grant).

Funding Information:
We thank the University of Minnesota Imaging Center (Marker Sanders, Gail Celio, Guillermo Marques, and Thomas Pengo), the Center for Mass Spectrometry and Proteomics (Candace Guerrero), the Mayo Clinic Microscopy and Cell Analysis Core Facility (Trace Christensen and Jeffrey Salisbury), and the University of Iowa Metabolomics Core Facility for providing instrumentation and expertise. We thank Mahima Devarajan, Ann Hertzel, and David Berhnlor for scientific discussions and Margaret Harter for technical assistance. Funding was provided for C.N. (NIH: T32AG029796, K99AG070104, AHA: 20POST35180115), T.D.H. (NIH: K01DK125258), E.W.K. (NIH: T32DK007203), E.B.T. (NIH: R01DK104998 and University of Iowa Healthcare Distinguished Scholars Award), E.M.P. (NIH: R21GM127965), and D.G.M. (NIH: R01DK132849 and R01DK114401 and the University of Minnesota Institute on Diabetes and Obesity and the University of Iowa Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility grant). 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. The authors declare no competing interests.

Publisher Copyright:
© 2023 The Authors

Keywords

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

PubMed: MeSH publication types

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

Publisher link

10.1016/j.celrep.2023.112435

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Najt, C. P., Adhikari, S., Heden, T. D., Cui, W., Gansemer, E. R., Rauckhorst, A. J., Markowski, T. W., Higgins, L. A., Kerr, E. W., Boyum, M. D., Alvarez, J., Brunko, S., Mehra, D., Puchner, E. M., Taylor, E. B., & Mashek, D. G. (2023). Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism. Cell reports, 42(5), Article 112435. https://doi.org/10.1016/j.celrep.2023.112435

@article{1ae47f5cddd54b36b413c9ec1c4d1ecc,

title = "Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism",

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, cytosolic mitochondria, fatty acids, lipid anabolism, lipid catabolism, lipid droplets, MAM, organelle interactions, peridroplet mitochondria, perilipin 5, single-molecule localization microscopy",

author = "Najt, {Charles P.} and Santosh Adhikari and Heden, {Timothy D.} and Wenqi Cui and Gansemer, {Erica R.} and Rauckhorst, {Adam J.} and Markowski, {Todd W.} and Higgins, {Lee Ann} and Kerr, {Evan W.} and Boyum, {Matthew D.} and Jonas Alvarez and Sophia Brunko and Dushyant Mehra and Puchner, {Elias M.} and Taylor, {Eric B.} and Mashek, {Douglas G.}",

note = "Funding Information: We thank the University of Minnesota Imaging Center (Marker Sanders, Gail Celio, Guillermo Marques, and Thomas Pengo), the Center for Mass Spectrometry and Proteomics (Candace Guerrero), the Mayo Clinic Microscopy and Cell Analysis Core Facility (Trace Christensen and Jeffrey Salisbury), and the University of Iowa Metabolomics Core Facility for providing instrumentation and expertise. We thank Mahima Devarajan, Ann Hertzel, and David Berhnlor for scientific discussions and Margaret Harter for technical assistance. Funding was provided for C.N. ( NIH : T32AG029796 , K99AG070104 , AHA: 20POST35180115 ), T.D.H. ( NIH : K01DK125258 ), E.W.K. ( NIH : T32DK007203 ), E.B.T. ( NIH : R01DK104998 and University of Iowa Healthcare Distinguished Scholars Award), E.M.P. ( NIH : R21GM127965 ), and D.G.M. ( NIH : R01DK132849 and R01DK114401 and the University of Minnesota Institute on Diabetes and Obesity and the University of Iowa Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility grant). Funding Information: We thank the University of Minnesota Imaging Center (Marker Sanders, Gail Celio, Guillermo Marques, and Thomas Pengo), the Center for Mass Spectrometry and Proteomics (Candace Guerrero), the Mayo Clinic Microscopy and Cell Analysis Core Facility (Trace Christensen and Jeffrey Salisbury), and the University of Iowa Metabolomics Core Facility for providing instrumentation and expertise. We thank Mahima Devarajan, Ann Hertzel, and David Berhnlor for scientific discussions and Margaret Harter for technical assistance. Funding was provided for C.N. (NIH: T32AG029796, K99AG070104, AHA: 20POST35180115), T.D.H. (NIH: K01DK125258), E.W.K. (NIH: T32DK007203), E.B.T. (NIH: R01DK104998 and University of Iowa Healthcare Distinguished Scholars Award), E.M.P. (NIH: R21GM127965), and D.G.M. (NIH: R01DK132849 and R01DK114401 and the University of Minnesota Institute on Diabetes and Obesity and the University of Iowa Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility grant). 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. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = may,

day = "30",

doi = "10.1016/j.celrep.2023.112435",

language = "English (US)",

volume = "42",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

AU - Najt, Charles P.

AU - Adhikari, Santosh

AU - Heden, Timothy D.

AU - Cui, Wenqi

AU - Gansemer, Erica R.

AU - Rauckhorst, Adam J.

AU - Markowski, Todd W.

AU - Higgins, Lee Ann

AU - Kerr, Evan W.

AU - Boyum, Matthew D.

AU - Alvarez, Jonas

AU - Brunko, Sophia

AU - Mehra, Dushyant

AU - Puchner, Elias M.

AU - Taylor, Eric B.

AU - Mashek, Douglas G.

N1 - Funding Information: We thank the University of Minnesota Imaging Center (Marker Sanders, Gail Celio, Guillermo Marques, and Thomas Pengo), the Center for Mass Spectrometry and Proteomics (Candace Guerrero), the Mayo Clinic Microscopy and Cell Analysis Core Facility (Trace Christensen and Jeffrey Salisbury), and the University of Iowa Metabolomics Core Facility for providing instrumentation and expertise. We thank Mahima Devarajan, Ann Hertzel, and David Berhnlor for scientific discussions and Margaret Harter for technical assistance. Funding was provided for C.N. ( NIH : T32AG029796 , K99AG070104 , AHA: 20POST35180115 ), T.D.H. ( NIH : K01DK125258 ), E.W.K. ( NIH : T32DK007203 ), E.B.T. ( NIH : R01DK104998 and University of Iowa Healthcare Distinguished Scholars Award), E.M.P. ( NIH : R21GM127965 ), and D.G.M. ( NIH : R01DK132849 and R01DK114401 and the University of Minnesota Institute on Diabetes and Obesity and the University of Iowa Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility grant). Funding Information: We thank the University of Minnesota Imaging Center (Marker Sanders, Gail Celio, Guillermo Marques, and Thomas Pengo), the Center for Mass Spectrometry and Proteomics (Candace Guerrero), the Mayo Clinic Microscopy and Cell Analysis Core Facility (Trace Christensen and Jeffrey Salisbury), and the University of Iowa Metabolomics Core Facility for providing instrumentation and expertise. We thank Mahima Devarajan, Ann Hertzel, and David Berhnlor for scientific discussions and Margaret Harter for technical assistance. Funding was provided for C.N. (NIH: T32AG029796, K99AG070104, AHA: 20POST35180115), T.D.H. (NIH: K01DK125258), E.W.K. (NIH: T32DK007203), E.B.T. (NIH: R01DK104998 and University of Iowa Healthcare Distinguished Scholars Award), E.M.P. (NIH: R21GM127965), and D.G.M. (NIH: R01DK132849 and R01DK114401 and the University of Minnesota Institute on Diabetes and Obesity and the University of Iowa Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility grant). 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. The authors declare no competing interests. Publisher Copyright: © 2023 The Authors

PY - 2023/5/30

Y1 - 2023/5/30

N2 - 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.

AB - 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.

KW - CP: Metabolism

KW - cytosolic mitochondria

KW - fatty acids

KW - lipid anabolism

KW - lipid catabolism

KW - lipid droplets

KW - MAM

KW - organelle interactions

KW - peridroplet mitochondria

KW - perilipin 5

KW - single-molecule localization microscopy

UR - http://www.scopus.com/inward/record.url?scp=85153520532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85153520532&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112435

DO - 10.1016/j.celrep.2023.112435

M3 - Article

C2 - 37104088

AN - SCOPUS:85153520532

SN - 2211-1247

VL - 42

JO - Cell reports

JF - Cell reports

IS - 5

M1 - 112435

ER -

Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Abstract

Bibliographical note

Keywords

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Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Abstract

Bibliographical note

Keywords

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