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

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

doi:10.1016/j.celrep.2021.110213

Cited by 45 publications

(52 citation statements)

References 70 publications

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“…Food intake was not increased. Finally, tamoxifen-inducible seipin deletion under the ERT2-AdipoQ promoter also induces a progressive loss of adipose tissue, strongly supporting that seipin is required for mature adipocyte maintenance [ 45 , 46 ].…”

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

“…Together with the increased NEFA release, several studies reported an increase in FA oxidation and thermogenesis [ 45 , 56 ] in seipin-deficient WAT. Recently, using an inducible deletion of seipin, we reported that this induction of FA catabolism was transitory, suggesting that it may be an early event accounting for the loss of TAG store in seipin-deficient adipose tissue [ 46 ]. Altogether, several pieces of evidence support that abnormally elevated NEFA release and catabolism might contribute to the lipodystrophic phenotype of seipin-deficient mice.…”

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

“…Nevertheless, the function of seipin in mature adipocytes remains incompletely understood, and several elements need to be clarified. In 3T3-L1 adipocytes, we have shown that seipin is enriched at ER/LD contact sites under lipid loading and alternatively localizes at the ER/mitochondria contact sites also named MAMs [ 46 ]. Seipin interacts with MAM-associated calcium regulators, and seipin deficiency alters the ER to mitochondria Ca 2+ flux, and this reduction is associated with a decrease in ATP production that is known to be dependent on mitochondrial Ca 2+ levels [ 46 ].…”

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

“…In 3T3-L1 adipocytes, we have shown that seipin is enriched at ER/LD contact sites under lipid loading and alternatively localizes at the ER/mitochondria contact sites also named MAMs [ 46 ]. Seipin interacts with MAM-associated calcium regulators, and seipin deficiency alters the ER to mitochondria Ca 2+ flux, and this reduction is associated with a decrease in ATP production that is known to be dependent on mitochondrial Ca 2+ levels [ 46 ]. These data are consistent with the work performed by Huang’s lab that demonstrated in drosophila cells that seipin regulates ER Ca 2+ handling [ 63 , 64 ].…”

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

“…Finally, seipin deficiency in mature adipocytes induces the expression of ER stress markers including the pro-apoptotic C/EBP homologous protein (CHOP) transcription factor [ 43 , 46 ]. Therefore, ER stress might be one of the mechanisms involved in adipocyte loss.…”

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

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Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Magré

Prieur

2022

IJMS

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Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.

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Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

Section: Seipin Deficiency Leads To Severe Lipodystrophymentioning

confidence: 99%

See 3 more Smart Citations

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Magré

Prieur

2022

IJMS

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Emerging functions of the mitochondria–ER–lipid droplet three‐way junction in coordinating lipid transfer, metabolism, and storage in cells

Monteiro‐Cardoso,

Giordano

2024

FEBS Letters

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Over the past two decades, we have witnessed a growing appreciation for the importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where the membranes of two organelles meet but do not fuse and allow the transfer of metabolites between organelles, playing crucial roles in the coordination of cellular metabolic activities. The significant advancements in imaging techniques and molecular and cell biology research have revealed that CS are more complex than what originally thought, and as they are extremely dynamic, they can remodel their shape, composition, and functions in accordance with metabolic and environmental changes and can occur between more than two organelles. Here, we describe how recent studies led to the identification of a three‐way mitochondria–ER–lipid droplet CS and discuss the emerging functions of these contacts in maintaining lipid storage, homeostasis, and balance. We also summarize the properties and functions of key protein components localized at the mitochondria–ER–lipid droplet interface, with a special focus on lipid transfer proteins. Understanding tripartite CS is essential for unraveling the complexities of inter‐organelle communication and cooperation within cells.

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Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Cao

Tian

Zhang

et al. 2023

MedComm

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Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID‐19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.

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

Cited by 45 publications

References 70 publications

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Emerging functions of the mitochondria–ER–lipid droplet three‐way junction in coordinating lipid transfer, metabolism, and storage in cells

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

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