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 |
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Article number | 110213 |
Number of pages | 25 |
Journal | Cell Reports |
Volume | 38 |
Issue number | 2 |
DOIs | |
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