Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Malek, Mouhannad; Wawrzyniak, Anna Maria; Koch, Peter; Lüchtenborg, Christian; Hessenberger, Manuel; Sachsenheimer, Timo; Jang, Wonyul; Bruegger, Britta; Haucke, Volker

doi:10.1038/s41467-021-22882-x

Cited by 34 publications

(20 citation statements)

References 86 publications

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“…Further, a key question that remains unanswered is whether alterations in intracellular Ca 2+ signaling are purely deleterious sequences (see paragraph below) or are part of a molecular mechanism(s) attempting to correct the cellular phenotypes of NPC1 disease. There are clear links between elevations in intracellular Ca 2+ levels and endocytic fusion and transport events; further, decreasing Ca 2+ ER has been reported to redistribute the intracellular pool of unesterified cholesterol ( 43 ) and rescue key cellular phenotypes of NPC1 disease ( 6 ), while knocking out INPP5A ( 44 ) (IP 3 5-phosphatase) triggers depletion of cellular cholesterol. Thus, changes in Ca 2+ ER signaling may be a key rheostat for maintenance and control of cellular cholesterol homeostasis.…”

Section: Discussionmentioning

confidence: 99%

IP ₃ R-driven increases in mitochondrial Ca ²⁺ promote neuronal death in NPC disease

Tiscione

Casas

Horvath

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease–causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor–stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.

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Section: Discussionmentioning

confidence: 99%

IP ₃ R-driven increases in mitochondrial Ca ²⁺ promote neuronal death in NPC disease

Tiscione

Casas

Horvath

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…In yeast, starvation-induced cytosol acidification alters the protonation state of the head group of PtdIns4P, thereby impairing Osh1/OSBP-mediated sterol transfer and protein sorting at the TGN 34 . In mammalian cells, Ins(1,4,5)P 3 -triggered calcium efflux from ER stores downstream of receptor signalling causes OSBP to dissociate from the TGN, resulting in the depletion of cholesterol and associated glycolipids from the cell surface 173 , while promoting the formation of E-Syt-based MCSs between the ER and the plasma membrane 158 . Hence, distinct MCSs may be subject to antagonistically controlled mechanisms of regulation.…”

Section: Membrane Contact Sitesmentioning

confidence: 99%

Phosphoinositides as membrane organizers

Posor

Jang

Haucke

2022

Nat Rev Mol Cell Biol

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209

128

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Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially discovered for their roles in cell signalling, phosphoinositides are now widely recognized as key integrators of membrane dynamics that broadly impact on all aspects of cell physiology and on disease. The past decade has witnessed a vast expansion of our knowledge of phosphoinositide biology. On the endocytic and exocytic routes, phosphoinositides direct the inward and outward flow of membrane as vesicular traffic is coupled to the conversion of phosphoinositides. Moreover, recent findings on the roles of phosphoinositides in autophagy and the endolysosomal system challenge our view of lysosome biology. The non-vesicular exchange of lipids, ions and metabolites at membrane contact sites in between organelles has also been found to depend on phosphoinositides. Here we review our current understanding of how phosphoinositides shape and direct membrane dynamics to impact on cell physiology, and provide an overview of emerging concepts in phosphoinositide regulation.

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“…Phosphatidylserine (PS) is a glycerophospholipid resided in the cytoplasm ( Malek et al, 2021 ). PS is synthesized by phosphatidylserine synthase 1 (PSS1) and phosphatidylserine synthase 2 (PSS2), which are localized on MERCs ( Kuge and Nishijima, 1997 ; Vance, 2014 ).…”

Section: Biological Functions Of Mercsmentioning

confidence: 99%

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Mitochondrial and endoplasmic reticulum (ER) are important intracellular organelles. The sites that mitochondrial and ER are closely related in structure and function are called Mitochondria-ER contacts (MERCs). MERCs are involved in a variety of biological processes, including calcium signaling, lipid synthesis and transport, autophagy, mitochondrial dynamics, ER stress, and inflammation. Sepsis-induced myocardial dysfunction (SIMD) is a vital organ damage caused by sepsis, which is closely associated with mitochondrial and ER dysfunction. Growing evidence strongly supports the role of MERCs in the pathogenesis of SIMD. In this review, we summarize the biological functions of MERCs and the roles of MERCs proteins in SIMD.

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Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Cited by 34 publications

References 86 publications

IP ₃ R-driven increases in mitochondrial Ca ²⁺ promote neuronal death in NPC disease

IP ₃ R-driven increases in mitochondrial Ca ²⁺ promote neuronal death in NPC disease

Phosphoinositides as membrane organizers

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction

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Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Cited by 34 publications

References 86 publications

IP 3 R-driven increases in mitochondrial Ca 2+ promote neuronal death in NPC disease

IP 3 R-driven increases in mitochondrial Ca 2+ promote neuronal death in NPC disease

Phosphoinositides as membrane organizers

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction

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Product

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IP ₃ R-driven increases in mitochondrial Ca ²⁺ promote neuronal death in NPC disease

IP ₃ R-driven increases in mitochondrial Ca ²⁺ promote neuronal death in NPC disease