Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

Malgorzata Zatyka; Tatiana R Rosenstock; Congxin Sun; Adina M Palhegyi; Georgina W Hughes; Samuel Lara-Reyna; Dewi Astuti; Alessandro di Maio; Axel Sciauvaud; Miriam E Korsgen; Vesna Stanulovic; Gamze Kocak; Malgorzata Rak; Sandra Pourtoy-Brasselet; Katherine Winter; Thiago Varga; Margot Jarrige; Hélène Polvèche; Joao Correia; Eva-Maria Frickel; Maarten Hoogenkamp; Douglas G Ward; Laetitia Aubry; Timothy Barrett; Sovan Sarkar

doi:10.1016/j.stemcr.2023.04.002

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

Malgorzata Zatyka, Tatiana R Rosenstock, Congxin Sun, Adina M Palhegyi, Georgina W Hughes, Samuel Lara-Reyna, Dewi Astuti, Alessandro di Maio, Axel Sciauvaud, Miriam E Korsgen, Vesna Stanulovic, Gamze Kocak, Malgorzata Rak, Sandra Pourtoy-Brasselet, Katherine Winter, Thiago Varga, Margot Jarrige, Hélène Polvèche, Joao Correia, Eva-Maria FrickelMaarten Hoogenkamp, Douglas G Ward, Laetitia Aubry, Timothy Barrett, Sovan Sarkar^*

^*Corresponding author for this work

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Abstract

Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.

Original language	English
Pages (from-to)	1090-1106
Number of pages	17
Journal	Stem Cell Reports
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.stemcr.2023.04.002
Publication status	Published - 9 May 2023

Bibliographical note

Funding Information:
This study was supported by LifeArc Philanthropic Fund (P2019-0004), LifeArc Pathfinder Award, along with Wellcome Trust Seed Award (109626/Z/15/Z), Wellcome Trust ISSF (1516ISSFFEL10), UKIERI DST Thematic Partnership Award (2016-17-0087), and Birmingham Fellowship to S.S. University of Birmingham (UoB) Brazil Visiting Fellowship, FAPESP-UoB Strategic Collaboration Fund, and Rutherford Fellowship to S.S. and T.R.R. BBSRC and UoB-funded MIBTP Studentship (BB/T00746X/1) to M.E.K. and S.S. FAPESP grant (2015/02041-1) to T.R.R. Wellcome Trust Senior Research Fellowship (217202/Z/19/Z) to E.M.F. Agence Nationale de la Recherche: Labex REVIVE (ANR-10-LABX-73) to L.A. and MRC DPFS (MR/P007732/1) to T.B. We thank New York Stem Cell Foundation for providing WS1 and WS2 hiPSC lines, R. Jaenisch for providing WIBR3 hESC line, J. Barlow and UoB Mitochondrial Profiling Center for technical support and the use of Seahorse facility, and M. Coleman for the use of microplate reader. T.R.R. is also a Volunteer Professor at University of São Paulo, Brazil. T.B. is an NIHR Senior Investigator. S.S. is also Former Fellow for life at Hughes Hall, University of Cambridge, UK. The authors declare no competing interests.

Publisher Copyright:
© 2023 The Author(s)

Keywords

Wolfram syndrome
WFS1
Mitochondrial dysfunction
Mitochondrial membrane potential
VDAC1
Mitochondria-associated ER membrane
Human induced pluripotent stem cell-derived neurons
Neurodegeneration
Cyclosporin A
MnTBAP

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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ZatykaM2023DepletionFinal published version, 8.16 MBLicence: Creative Commons: Attribution (CC BY)

1 Finished
1 Active

Development of a novel repurposed drug treatment for neurodegeneration and diabetes in Wolfram syndrome
Nagy, Z. (Co-Investigator), Peet, A. (Co-Investigator), Brock, K. (Co-Investigator), Barrett, T. (Principal Investigator) & Martin, U. (Co-Investigator)
Medical Research Council
1/03/17 → 28/02/25
Project: Research Councils
Human cellular platforms for studying the regulation and therapeutic application of autophagy
Sarkar, S. (Principal Investigator)
Wellcome Trust
1/07/16 → 31/12/18
Project: Research

Cite this

Zatyka, M., Rosenstock, T. R., Sun, C., Palhegyi, A. M., Hughes, G. W., Lara-Reyna, S., Astuti, D., di Maio, A., Sciauvaud, A., Korsgen, M. E., Stanulovic, V., Kocak, G., Rak, M., Pourtoy-Brasselet, S., Winter, K., Varga, T., Jarrige, M., Polvèche, H., Correia, J., ... Sarkar, S. (2023). Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome. Stem Cell Reports, 18(5), 1090-1106. https://doi.org/10.1016/j.stemcr.2023.04.002

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title = "Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome",

abstract = "Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.",

keywords = "Wolfram syndrome, WFS1, Mitochondrial dysfunction, Mitochondrial membrane potential, VDAC1, Mitochondria-associated ER membrane, Human induced pluripotent stem cell-derived neurons, Neurodegeneration, Cyclosporin A, MnTBAP",

author = "Malgorzata Zatyka and Rosenstock, {Tatiana R} and Congxin Sun and Palhegyi, {Adina M} and Hughes, {Georgina W} and Samuel Lara-Reyna and Dewi Astuti and {di Maio}, Alessandro and Axel Sciauvaud and Korsgen, {Miriam E} and Vesna Stanulovic and Gamze Kocak and Malgorzata Rak and Sandra Pourtoy-Brasselet and Katherine Winter and Thiago Varga and Margot Jarrige and H{\'e}l{\`e}ne Polv{\`e}che and Joao Correia and Eva-Maria Frickel and Maarten Hoogenkamp and Ward, {Douglas G} and Laetitia Aubry and Timothy Barrett and Sovan Sarkar",

note = "Funding Information: This study was supported by LifeArc Philanthropic Fund (P2019-0004), LifeArc Pathfinder Award, along with Wellcome Trust Seed Award (109626/Z/15/Z), Wellcome Trust ISSF (1516ISSFFEL10), UKIERI DST Thematic Partnership Award (2016-17-0087), and Birmingham Fellowship to S.S. University of Birmingham (UoB) Brazil Visiting Fellowship, FAPESP-UoB Strategic Collaboration Fund, and Rutherford Fellowship to S.S. and T.R.R. BBSRC and UoB-funded MIBTP Studentship (BB/T00746X/1) to M.E.K. and S.S. FAPESP grant (2015/02041-1) to T.R.R. Wellcome Trust Senior Research Fellowship (217202/Z/19/Z) to E.M.F. Agence Nationale de la Recherche: Labex REVIVE (ANR-10-LABX-73) to L.A. and MRC DPFS (MR/P007732/1) to T.B. We thank New York Stem Cell Foundation for providing WS1 and WS2 hiPSC lines, R. Jaenisch for providing WIBR3 hESC line, J. Barlow and UoB Mitochondrial Profiling Center for technical support and the use of Seahorse facility, and M. Coleman for the use of microplate reader. T.R.R. is also a Volunteer Professor at University of S{\~a}o Paulo, Brazil. T.B. is an NIHR Senior Investigator. S.S. is also Former Fellow for life at Hughes Hall, University of Cambridge, UK. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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month = may,

day = "9",

doi = "10.1016/j.stemcr.2023.04.002",

language = "English",

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Zatyka, M, Rosenstock, TR, Sun, C, Palhegyi, AM, Hughes, GW, Lara-Reyna, S, Astuti, D, di Maio, A, Sciauvaud, A, Korsgen, ME, Stanulovic, V , Kocak, G, Rak, M, Pourtoy-Brasselet, S, Winter, K, Varga, T, Jarrige, M, Polvèche, H, Correia, J, Frickel, E-M , Hoogenkamp, M , Ward, DG, Aubry, L, Barrett, T & Sarkar, S 2023, 'Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome', Stem Cell Reports, vol. 18, no. 5, pp. 1090-1106. https://doi.org/10.1016/j.stemcr.2023.04.002

TY - JOUR

T1 - Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

AU - Zatyka, Malgorzata

AU - Rosenstock, Tatiana R

AU - Sun, Congxin

AU - Palhegyi, Adina M

AU - Hughes, Georgina W

AU - Lara-Reyna, Samuel

AU - Astuti, Dewi

AU - di Maio, Alessandro

AU - Sciauvaud, Axel

AU - Korsgen, Miriam E

AU - Stanulovic, Vesna

AU - Kocak, Gamze

AU - Rak, Malgorzata

AU - Pourtoy-Brasselet, Sandra

AU - Winter, Katherine

AU - Varga, Thiago

AU - Jarrige, Margot

AU - Polvèche, Hélène

AU - Correia, Joao

AU - Frickel, Eva-Maria

AU - Hoogenkamp, Maarten

AU - Ward, Douglas G

AU - Aubry, Laetitia

AU - Barrett, Timothy

AU - Sarkar, Sovan

N1 - Funding Information: This study was supported by LifeArc Philanthropic Fund (P2019-0004), LifeArc Pathfinder Award, along with Wellcome Trust Seed Award (109626/Z/15/Z), Wellcome Trust ISSF (1516ISSFFEL10), UKIERI DST Thematic Partnership Award (2016-17-0087), and Birmingham Fellowship to S.S. University of Birmingham (UoB) Brazil Visiting Fellowship, FAPESP-UoB Strategic Collaboration Fund, and Rutherford Fellowship to S.S. and T.R.R. BBSRC and UoB-funded MIBTP Studentship (BB/T00746X/1) to M.E.K. and S.S. FAPESP grant (2015/02041-1) to T.R.R. Wellcome Trust Senior Research Fellowship (217202/Z/19/Z) to E.M.F. Agence Nationale de la Recherche: Labex REVIVE (ANR-10-LABX-73) to L.A. and MRC DPFS (MR/P007732/1) to T.B. We thank New York Stem Cell Foundation for providing WS1 and WS2 hiPSC lines, R. Jaenisch for providing WIBR3 hESC line, J. Barlow and UoB Mitochondrial Profiling Center for technical support and the use of Seahorse facility, and M. Coleman for the use of microplate reader. T.R.R. is also a Volunteer Professor at University of São Paulo, Brazil. T.B. is an NIHR Senior Investigator. S.S. is also Former Fellow for life at Hughes Hall, University of Cambridge, UK. The authors declare no competing interests. Publisher Copyright: © 2023 The Author(s)

PY - 2023/5/9

Y1 - 2023/5/9

N2 - Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.

AB - Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.

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KW - WFS1

KW - Mitochondrial dysfunction

KW - Mitochondrial membrane potential

KW - VDAC1

KW - Mitochondria-associated ER membrane

KW - Human induced pluripotent stem cell-derived neurons

KW - Neurodegeneration

KW - Cyclosporin A

KW - MnTBAP

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U2 - 10.1016/j.stemcr.2023.04.002

DO - 10.1016/j.stemcr.2023.04.002

M3 - Article

C2 - 37163979

SN - 2213-6711

VL - 18

SP - 1090

EP - 1106

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 5

ER -

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Projects

Development of a novel repurposed drug treatment for neurodegeneration and diabetes in Wolfram syndrome

Human cellular platforms for studying the regulation and therapeutic application of autophagy

Cite this