A computational model of lysosome-ER Ca2+ microdomains

Penny, C.; Kilpatrick, Bethan S.; Han, Jung Min; Sneyd, James; Patel, Sandip

doi:10.1242/jcs.149047

Cited by 61 publications

(57 citation statements)

References 73 publications

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“…We confirmed lysosomal Ca 2+ reduction by assaying Ca 2+ release after pretreatment with ionomycin to release all internal, non-lysosomal calcium stores (Lloyd-Evans et al, 2008), followed by glycyl-L-phenylalanine-beta-naphthylamide (GPN) to induce lysosomal rupture causing the release of lysosomal Ca 2+ (Penny et al, 2014). Interestingly, GPN elevated cytosolic Ca 2+ due to lysosomal Ca 2+ release after ionomycin treatment in WT, but had minimal effect on PS1KO cells (Fig 1B).…”

Section: Resultsmentioning

confidence: 70%

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

et al. 2015

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Summary Presenilin-1 (PS1) deletion or Alzheimer’s Disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in PS1KO cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss of function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.

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Section: Resultsmentioning

confidence: 70%

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

et al. 2015

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“…Mathematical modeling supports this concept. Simulation of Ca 2+ fluxes at ER-lysosome MCSs in fibroblasts [45] and SR-lysosome MCSs in pulmonary artery smooth muscle cells [17] predict that lysosomal Ca 2+ release is sufficient to trigger Ca 2+ induced Ca 2+ release from the ER/SR. It is also probable that ER MCSs with the endocytic pathway might function in the generation/ amplification of the localized Ca 2 + signals required for endosomelysosome fusion.…”

Section: Er-endocytic Pathway Mcssmentioning

confidence: 99%

Calcium signaling at ER membrane contact sites

Burgoyne¹,

Patel

Eden³

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Communication between organelles is a necessary consequence of intracellular compartmentalization. Membrane contact sites (MCSs) are regions where the membranes of two organelles come into close apposition allowing exchange of small molecules and ions including Ca²⁺. The ER, the cell's major Ca²⁺ store, forms an extensive and dynamic network of contacts with multiple organelles. Here we review established and emerging roles of ER contacts as platforms for Ca²⁺ exchange and further consider a potential role for Ca²⁺ in the regulation of MCS formation. We additionally discuss the challenges associated with the study of MCS biology and highlight advances in microscopy-based solutions. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

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“…Such a requirement for Ca 2+ is somewhat controversial, as is the issue of whether Ca 2+ is directly sourced from TPC activity [34]. However, the consistent demonstration of these chelator effects merits further consideration of the role of local TPC-evoked Ca 2+ microdomains that probably exist beneath the resolution of the conventional confocal imaging approaches applied to date [71]. Perhaps a small but significant Ca 2+ flux through TPCs [14,29–32] provides an intimate signal-regulating fusion of closely apposed endolysosomal structures.…”

Section: Tpcs and Regulation Of Traffickingmentioning

confidence: 99%

Two-pore channels at the intersection of endolysosomal membrane traffic

Marchant

Patel

2015

Biochemical Society Transactions

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Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that localize to acidic organelles such as lysosomes. The TPC complex is the proposed target of the Ca2 +-mobilizing messenger NAADP, which releases Ca2 + from these acidic Ca2 + stores. Whereas details of TPC activation and native ion permeation remain unclear, a consensus has emerged around their function in regulating endolysosomal trafficking. This role is supported by recent proteomic data showing that TPCs interact with proteins controlling membrane organization and dynamics, including Rab GTPases and components of the fusion apparatus. Regulation of TPCs by PtdIns(3,5)P2 and/or NAADP (nicotinic acid adenine dinucleotide phosphate) together with their functional and physical association with Rab proteins provides a mechanism for coupling phosphoinositide and trafficking protein cues to local ion fluxes. Therefore, TPCs work at the regulatory cross-roads of (patho)physiological cues to co-ordinate and potentially deregulate traffic flow through the endolysosomal network. This review focuses on the native role of TPCs in trafficking and their emerging contributions to endolysosomal trafficking dysfunction.

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A computational model of lysosome-ER Ca2+ microdomains

Abstract: ABSTRACT

Cited by 61 publications

References 73 publications

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

Calcium signaling at ER membrane contact sites

Two-pore channels at the intersection of endolysosomal membrane traffic

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