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

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

25 Citeringar (Scopus)
29 Nedladdningar (Pure)

Sammanfattning

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.

OriginalspråkEngelska
Artikelnummer110213
Antal sidor25
TidskriftCell Reports
Volym38
Nummer2
DOI
StatusPublicerad - 11 jan. 2022
MoE-publikationstypA1 Tidskriftsartikel-refererad

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