Gomez-Suaga, Patricia

Miller, Christopher C.J.

Paillusson, Sebastien

Patricia Gomez-Suaga

Sebastien Paillusson

Christopher C. J. Miller

Crossref

Autophagy

ER-mitochondria signaling regulates autophagy

The endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several key cellular processes. The formation of these contacts involves “tethering proteins” that function to recruit regions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds to the outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) to form one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulate macroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosen ER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB or RMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria via expression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effects of VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed that the modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR (inositol 1,4,5-trisphosphate receptor) delivery of Ca2+ from ER stores to mitochondria.</p

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                       King’s Research Portal  DOI:10.1080/15548627.2017.1317913Document VersionPublisher's PDF, also known as Version of recordLink to publication record in King's Research PortalCitation for published version (APA):Gomez-Suaga, P., Paillusson, S., & Miller, C. C. J. (2017). ER-mitochondria signaling regulates autophagy.Autophagy, 1-2. https://doi.org/10.1080/15548627.2017.1317913Citing this paperPlease note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this maydiffer from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination,volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you areagain advised to check the publisher's website for any subsequent corrections.General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain•You may freely distribute the URL identifying the publication in the Research PortalTake down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access tothe work immediately and investigate your claim.Download date: 14. Oct. 2023Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=kaup20Download by: [King's College London] Date: 20 July 2017, At: 08:10AutophagyISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: http://www.tandfonline.com/loi/kaup20ER-mitochondria signaling regulates autophagyPatricia Gomez-Suaga , Sebastien Paillusson & Christopher C. J. MillerTo cite this article: Patricia Gomez-Suaga , Sebastien Paillusson & Christopher C.J. Miller (2017): ER-mitochondria signaling regulates autophagy, Autophagy, DOI:10.1080/15548627.2017.1317913To link to this article:  http://dx.doi.org/10.1080/15548627.2017.1317913© 2017 The Author(s). Published withlicense by Taylor & Francis© PatriciaGomez-Suaga, Sebastien Paillusson, andChristopher C. J. MillerAccepted author version posted online: 26May 2017.Published online: 26 May 2017.Submit your article to this journal Article views: 718View related articles View Crossmark dataAUTOPHAGIC PUNCTUMER-mitochondria signaling regulates autophagyPatricia Gomez-Suaga , Sebastien Paillusson, and Christopher C. J. MillerDepartment of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UKARTICLE HISTORYReceived 21 March 2017Revised 24 March 2017Accepted 5 April 2017ABSTRACTThe endoplasmic reticulum (ER) and mitochondria form tight functional contacts that regulate several keycellular processes. The formation of these contacts involves “tethering proteins” that function to recruitregions of ER to mitochondria. The integral ER protein VAPB (VAMP associated protein B and C) binds tothe outer mitochondrial membrane protein, RMDN3/PTPIP51 (regulator of microtubule dynamics 3) toform one such set of tethers. Recently, we showed that the VAPB-RMDN3 tethers regulatemacroautophagy/autophagy. Small interfering RNA (siRNA) knockdown of VAPB or RMDN3 to loosenER-mitochondria contacts stimulates autophagosome formation, whereas overexpression of VAPB orRMDN3 to tighten contacts inhibit their formation. Artificial tethering of ER and mitochondria viaexpression of a synthetic linker protein also reduces autophagy and this artificial tether rescues the effectsof VAPB- or RMDN3-targeted siRNA loss on autophagosome formation. Finally, our studies revealed thatthe modulatory effects of ER-mitochondria contacts on autophagy involve their role in mediating ITPR(inositol 1,4,5-trisphosphate receptor) delivery of Ca2C from ER stores to mitochondria.KEYWORDSautophagy; calcium;endoplasmic reticulum;mitochondria; mitochondria-associated membranes;PTPIP51; VAPBSignaling between ER and mitochondria is now known to regu-late several fundamental physiological functions. This signalinginvolves close physical contacts between the 2 organelles suchthat up to approximately 20% of the mitochondrial surface isclosely apposed to ER membranes. The regions of ER in contactwith mitochondria are termed mitochondria-associated mem-branes (MAMs). The mechanisms by which ER membranes arerecruited to mitochondria are not properly known but one routeinvolves binding of the integral ER protein VAPB to the outermitochondrial membrane protein RMDN3. VAPB and RMDN3thus act as molecular scaffolds to tether the 2 organelles.Our recent studies showed that experimental manipulationof VAPB and RMDN3 expression to increase and decreaseER-mitochondria contacts markedly affects autophagy. Overex-pression of VAPB or RMDN3 to tighten ER-mitochondriacontacts, impairs basal and chemical (rapamycin and Torin1)-induced autophagy by decreasing autophagosome formation.In contrast, siRNA-mediated loss of VAPB or RMDN3 toloosen contacts causes an induction of autophagy flux with aconcomitant increase in the number of autophagic structures.Importantly, this VAPB and RMDN3 siRNA-mediated stimu-lation of autophagy is rescued by expression of a syntheticlinker protein that artificially tethers ER and mitochondria.Thus, these effects of VAPB and RMDN3 manipulation onautophagy are a consequence of their ER-mitochondria tether-ing function and not some as yet unknown alternative func-tion of VAPB and RMDN3.Interestingly, we discovered that while tightening ER-mito-chondria contacts by overexpression of VAPB or RMDN3impairs rapamycin- and Torin1-induced autophagy, it doesnot affect autophagy induced by starvation. This suggests thatthe regulation of autophagy by ER-mitochondria signaling isat least partly dependent upon the nature of the autophagicstimulus. Rapamycin and Torin1 induce autophagy by selec-tive inhibition of MTOR, whereas starvation-induced auto-phagy is a more complex mechanism involving a variety ofother nutrient-sensing molecules. Thus, the different effectsmay be due to differences in the signaling mechanism bywhich these stimuli induce autophagy.So how do the VAPB-RMDN3 tethers and ER-mitochondriasignaling generate this effect on autophagy? A primary functionof ER-mitochondria contacts is to facilitate ITPR-mediteddelivery of Ca2C from ER stores to mitochondria via VDAC(voltage dependent anion channel) and MCU (mitochondrialcalcium uniporter). This Ca2C is required by mitochondria forefficient ATP production because several dehydrogenases inthe TCA cycle are Ca2C-dependent. Thus, overexpression ofVAPB or RMDN3 to tighten ER-mitochondria contacts enhan-ces, whereas siRNA loss of VAPB or RMDN3 to loosen con-tacts inhibits Ca2C exchange. A number of previous studieshave shown that disruption of ITPR-mediated Ca2C deliverystimulates autophagy. Consistent with these findings, we foundthat blocking ER-mitochondria Ca2C exchange via ITPR antag-onists or MCU-targeted siRNAs abrogate the effects of VAPBCONTACT Christopher C. J. Miller chris.miller@kcl.ac.uk Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Instituteof Psychiatry, Psychology and Neuroscience, Kings College London, 125 Coldharbour Lane Camberwell, London, SE5 9NU, UK.Punctum to: Gomez-Suaga P, Paillusson S, Stoica R, Noble W, Hanger DP, Miller CCJ. The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy. CurrentBiology 2017; https://doi.org/10.1016/j.cub.2016.12.038.© 2017 Patricia Gomez-Suaga, Sebastien Paillusson, and Christopher C. J. Miller. Published with license by Taylor & Francis.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), whichpermits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.AUTOPHAGY2017, VOL. 13, NO. 7, 1–2https://doi.org/10.1080/15548627.2017.1317913and RMDN3 overexpression on autophagy. Thus the mecha-nism by which the VAPB-RMDN3 tethers regulates autophagyinvolves their role in facilitating ER-mitochondria Ca2Cexchange.A number of recent studies have demonstrated that damageto ER-mitochondria signaling occurs in neurodegenerative dis-eases such as Alzheimer and Parkinson diseases, and fronto-temporal dementia with related amyotrophic lateral sclerosis.Dysregulation of autophagy has also been linked to these disor-ders. Our findings will therefore facilitate future investigationson the role of autophagy in neurodegenerative diseases.Disclosure of potential conflicts of interestNo potential conflicts of interest were disclosed.FundingThis work was supported by Parkinson UK, Alzheimer’s Society,Alzheimer Research UK, MRC and the Wellcome Trust.ORCIDPatricia Gomez-Suaga http://orcid.org/0000-0002-2388-8327Figure 1. Diagram ilustrating the proposed mechanism by which the VAPB-RMDN3 ER-mitochondria tethering complex regulates autophagy. (A) VAPB orRMDN3 overexpression tightens ER-mitochondria contacts to enhance ITPR-medi-ated Ca2C delivery to mitochondria, which in turn inhibits autophagosome forma-tion. (B) siRNA-dependent loss of VAPB or RMDN3 loosens ER-mitochondriacontacts to inhibit Ca2C delivery and stimulate autophagosome formation.2 P. GOMEZ-SUAGA ET AL.

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ER-mitochondria signaling regulates autophagy

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