Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes

Yoann Combot; Veijo T Salo; Gilliane Chadeuf; Maarit Hölttä; Katharina Ven; Ilari Pulli; Simon Ducheix; Claire Pecqueur; Ophélie Renoult; Behnam Lak; Shiqian Li; Leena Karhinen; Ilya Belevich; Cedric Le May; Jennifer Rieusset; Soazig Le Lay; Mikael Croyal; Karim Si Tayeb; Helena Vihinen; Eija Jokitalo; Kid Törnquist; Corinne Vigouroux; Bertrand Cariou; Jocelyne Magré; Abdelhalim Larhlimi; Elina Ikonen; Xavier Prieur

doi:10.1016/j.celrep.2021.110213

Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes

Yoann Combot, Veijo T Salo, Gilliane Chadeuf, Maarit Hölttä, Katharina Ven, Ilari Pulli, Simon Ducheix, Claire Pecqueur, Ophélie Renoult, Behnam Lak, Shiqian Li, Leena Karhinen, Ilya Belevich, Cedric Le May, Jennifer Rieusset, Soazig Le Lay, Mikael Croyal, Karim Si Tayeb, Helena Vihinen, Eija JokitaloKid Törnquist, Corinne Vigouroux, Bertrand Cariou, Jocelyne Magré, Abdelhalim Larhlimi, Elina Ikonen, Xavier Prieur

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Abstract

Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.

Original language	English
Article number	110213
Number of pages	25
Journal	Cell Reports
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.110213
Publication status	Published - 11 Jan 2022
MoE publication type	A1 Journal article-refereed

Keywords

Adipocytes/metabolism
Adipose Tissue/metabolism
Animals
Calcium/metabolism
Cell Line
Endoplasmic Reticulum/metabolism
Endoplasmic Reticulum Stress
Energy Metabolism/physiology
GTP-Binding Protein gamma Subunits/deficiency
Humans
Lipid Droplets/metabolism
Lipid Metabolism/physiology
Lipids/physiology
Male
Mice
Mice, Inbred C57BL
Mitochondria/metabolism

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10.1016/j.celrep.2021.110213

PIIS2211124721017174Final published version, 5.36 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe202301031189

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Combot, Y., Salo, V. T., Chadeuf, G., Hölttä, M., Ven, K., Pulli, I., Ducheix, S., Pecqueur, C., Renoult, O., Lak, B., Li, S., Karhinen, L., Belevich, I., Le May, C., Rieusset, J., Le Lay, S., Croyal, M., Tayeb, K. S., Vihinen, H., ... Prieur, X. (2022). Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes. Cell Reports, 38(2), Article 110213. https://doi.org/10.1016/j.celrep.2021.110213

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title = "Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes",

abstract = "Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.",

keywords = "Adipocytes/metabolism, Adipose Tissue/metabolism, Animals, Calcium/metabolism, Cell Line, Endoplasmic Reticulum/metabolism, Endoplasmic Reticulum Stress, Energy Metabolism/physiology, GTP-Binding Protein gamma Subunits/deficiency, Humans, Lipid Droplets/metabolism, Lipid Metabolism/physiology, Lipids/physiology, Male, Mice, Mice, Inbred C57BL, Mitochondria/metabolism",

author = "Yoann Combot and Salo, {Veijo T} and Gilliane Chadeuf and Maarit H{\"o}ltt{\"a} and Katharina Ven and Ilari Pulli and Simon Ducheix and Claire Pecqueur and Oph{\'e}lie Renoult and Behnam Lak and Shiqian Li and Leena Karhinen and Ilya Belevich and {Le May}, Cedric and Jennifer Rieusset and {Le Lay}, Soazig and Mikael Croyal and Tayeb, {Karim Si} and Helena Vihinen and Eija Jokitalo and Kid T{\"o}rnquist and Corinne Vigouroux and Bertrand Cariou and Jocelyne Magr{\'e} and Abdelhalim Larhlimi and Elina Ikonen and Xavier Prieur",

year = "2022",

month = jan,

day = "11",

doi = "10.1016/j.celrep.2021.110213",

language = "English",

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Combot, Y, Salo, VT, Chadeuf, G, Hölttä, M, Ven, K, Pulli, I, Ducheix, S, Pecqueur, C, Renoult, O, Lak, B, Li, S, Karhinen, L, Belevich, I, Le May, C, Rieusset, J, Le Lay, S, Croyal, M, Tayeb, KS, Vihinen, H, Jokitalo, E, Törnquist, K, Vigouroux, C, Cariou, B, Magré, J, Larhlimi, A, Ikonen, E & Prieur, X 2022, 'Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes', Cell Reports, vol. 38, no. 2, 110213. https://doi.org/10.1016/j.celrep.2021.110213

TY - JOUR

T1 - Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes

AU - Combot, Yoann

AU - Salo, Veijo T

AU - Chadeuf, Gilliane

AU - Hölttä, Maarit

AU - Ven, Katharina

AU - Pulli, Ilari

AU - Ducheix, Simon

AU - Pecqueur, Claire

AU - Renoult, Ophélie

AU - Lak, Behnam

AU - Li, Shiqian

AU - Karhinen, Leena

AU - Belevich, Ilya

AU - Le May, Cedric

AU - Rieusset, Jennifer

AU - Le Lay, Soazig

AU - Croyal, Mikael

AU - Tayeb, Karim Si

AU - Vihinen, Helena

AU - Jokitalo, Eija

AU - Törnquist, Kid

AU - Vigouroux, Corinne

AU - Cariou, Bertrand

AU - Magré, Jocelyne

AU - Larhlimi, Abdelhalim

AU - Ikonen, Elina

AU - Prieur, Xavier

PY - 2022/1/11

Y1 - 2022/1/11

N2 - Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.

AB - Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.

KW - Adipocytes/metabolism

KW - Adipose Tissue/metabolism

KW - Animals

KW - Calcium/metabolism

KW - Cell Line

KW - Endoplasmic Reticulum/metabolism

KW - Endoplasmic Reticulum Stress

KW - Energy Metabolism/physiology

KW - GTP-Binding Protein gamma Subunits/deficiency

KW - Humans

KW - Lipid Droplets/metabolism

KW - Lipid Metabolism/physiology

KW - Lipids/physiology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitochondria/metabolism

U2 - 10.1016/j.celrep.2021.110213

DO - 10.1016/j.celrep.2021.110213

M3 - Article

C2 - 35021082

SN - 2211-1247

VL - 38

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 110213

ER -

Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes

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Keywords

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