Journal
CELL REPORTS
Volume 38, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.110213
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Funding
- Societe Francophone du Diabte
- FFRD (Federation Francaise des Diabetiques, Abbott, AstraZeneca, Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk)
- French National Research Agency [ANR-21-CE14-0024 MAMA, ANR-10-INBS-04]
- Academy of Finland [307415, 324929, 1331998]
- University of Helsinki/HiLIFE Fellowship
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Fondation Leducq [19CVD04]
- Ministere de l'Enseignement Superieur et de la Recherche
- Finnish Medical,
- Emil Aaltonen Foundation
- FEDER through the Operational Program for Competitiveness Factors and employment 2007-2013''
- Canceropole Ile-deFrance
- Academy of Finland (AKA) [324929, 324929] Funding Source: Academy of Finland (AKA)
- Agence Nationale de la Recherche (ANR) [ANR-21-CE14-0024] Funding Source: Agence Nationale de la Recherche (ANR)
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Deficiency of seipin, an ER protein, leads to mitochondrial abnormalities and dysfunctions in adipose tissue. Seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at ER-mitochondria contact sites (MAMs). Reduced ATP production in seipin-deficient adipose tissue contributes to the development of lipodystrophy.
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.
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