NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

Congxin Sun; Elena Seranova; Malkiel A. Cohen; Miruna Chipara; Jennie Roberts; Dewi Astuti; Adina M. Palhegyi; Animesh Acharjee; Lucia Sedlackova; Tetsushi Kataura; Elsje G. Otten; Prashanta K. Panda; Samuel Lara-Reyna; Miriam E. Korsgen; Kevin J. Kauffman; Alejandro Huerta-Uribe; Malgorzata Zatyka; Luiz F.S.E. Silva; Jorge Torresi; Shupei Zhang; Georgina W. Hughes; Carl Ward; Erich R. Kuechler; David Cartwright; Sergey Trushin; Eugenia Trushina; Gaurav Sahay; Yosef Buganim; Gareth G. Lavery; Joerg Gsponer; Daniel G. Anderson; Eva Maria Frickel; Tatiana R. Rosenstock; Timothy Barrett; Oliver D.K. Maddocks; Daniel A. Tennant; Haoyi Wang; Rudolf Jaenisch; Viktor I. Korolchuk; Sovan Sarkar

doi:10.1016/j.celrep.2023.112372

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

Congxin Sun, Elena Seranova, Malkiel A. Cohen, Miruna Chipara, Jennie Roberts, Dewi Astuti, Adina M. Palhegyi, Animesh Acharjee, Lucia Sedlackova, Tetsushi Kataura, Elsje G. Otten, Prashanta K. Panda, Samuel Lara-Reyna, Miriam E. Korsgen, Kevin J. Kauffman, Alejandro Huerta-Uribe, Malgorzata Zatyka, Luiz F.S.E. Silva, Jorge Torresi, Shupei ZhangGeorgina W. Hughes, Carl Ward, Erich R. Kuechler, David Cartwright, Sergey Trushin, Eugenia Trushina, Gaurav Sahay, Yosef Buganim, Gareth G. Lavery, Joerg Gsponer, Daniel G. Anderson, Eva Maria Frickel, Tatiana R. Rosenstock, Timothy Barrett, Oliver D.K. Maddocks, Daniel A. Tennant, Haoyi Wang, Rudolf Jaenisch, Viktor I. Korolchuk, Sovan Sarkar

Neurology

Research output: Contribution to journal › Article › peer-review

Abstract

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5^−/−) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5^−/− neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5^−/− neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5^−/− neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

Original language	English (US)
Article number	112372
Journal	Cell reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112372
State	Published - May 30 2023

Keywords

CP: Cell biology
CP: Metabolism
NAD
NADases
NAM
NMN
NR
autophagy
cell death
cell survival, human embryonic stem cell-derived neurons
mitochondria
nicotinamide
nicotinamide adenine dinucleotide
nicotinamide mononucleotide
nicotinamide riboside

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.112372

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Sun, C., Seranova, E., Cohen, M. A., Chipara, M., Roberts, J., Astuti, D., Palhegyi, A. M., Acharjee, A., Sedlackova, L., Kataura, T., Otten, E. G., Panda, P. K., Lara-Reyna, S., Korsgen, M. E., Kauffman, K. J., Huerta-Uribe, A., Zatyka, M., Silva, L. F. S. E., Torresi, J., ... Sarkar, S. (2023). NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency. Cell reports, 42(5), Article 112372. https://doi.org/10.1016/j.celrep.2023.112372

Sun, C, Seranova, E, Cohen, MA, Chipara, M, Roberts, J, Astuti, D, Palhegyi, AM, Acharjee, A, Sedlackova, L, Kataura, T, Otten, EG, Panda, PK, Lara-Reyna, S, Korsgen, ME, Kauffman, KJ, Huerta-Uribe, A, Zatyka, M, Silva, LFSE, Torresi, J, Zhang, S, Hughes, GW, Ward, C, Kuechler, ER, Cartwright, D, Trushin, S, Trushina, E, Sahay, G, Buganim, Y, Lavery, GG, Gsponer, J, Anderson, DG, Frickel, EM, Rosenstock, TR, Barrett, T, Maddocks, ODK, Tennant, DA, Wang, H, Jaenisch, R, Korolchuk, VI & Sarkar, S 2023, 'NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency', Cell reports, vol. 42, no. 5, 112372. https://doi.org/10.1016/j.celrep.2023.112372

@article{8918021e7d6f4617bc24ac51024d33f4,

title = "NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency",

abstract = "Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5−/− neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5−/− neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5−/− neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.",

keywords = "CP: Cell biology, CP: Metabolism, NAD, NADases, NAM, NMN, NR, autophagy, cell death, cell survival, human embryonic stem cell-derived neurons, mitochondria, nicotinamide, nicotinamide adenine dinucleotide, nicotinamide mononucleotide, nicotinamide riboside",

author = "Congxin Sun and Elena Seranova and Cohen, {Malkiel A.} and Miruna Chipara and Jennie Roberts and Dewi Astuti and Palhegyi, {Adina M.} and Animesh Acharjee and Lucia Sedlackova and Tetsushi Kataura and Otten, {Elsje G.} and Panda, {Prashanta K.} and Samuel Lara-Reyna and Korsgen, {Miriam E.} and Kauffman, {Kevin J.} and Alejandro Huerta-Uribe and Malgorzata Zatyka and Silva, {Luiz F.S.E.} and Jorge Torresi and Shupei Zhang and Hughes, {Georgina W.} and Carl Ward and Kuechler, {Erich R.} and David Cartwright and Sergey Trushin and Eugenia Trushina and Gaurav Sahay and Yosef Buganim and Lavery, {Gareth G.} and Joerg Gsponer and Anderson, {Daniel G.} and Frickel, {Eva Maria} and Rosenstock, {Tatiana R.} and Timothy Barrett and Maddocks, {Oliver D.K.} and Tennant, {Daniel A.} and Haoyi Wang and Rudolf Jaenisch and Korolchuk, {Viktor I.} and Sovan Sarkar",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

day = "30",

doi = "10.1016/j.celrep.2023.112372",

language = "English (US)",

volume = "42",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

AU - Sun, Congxin

AU - Seranova, Elena

AU - Cohen, Malkiel A.

AU - Chipara, Miruna

AU - Roberts, Jennie

AU - Astuti, Dewi

AU - Palhegyi, Adina M.

AU - Acharjee, Animesh

AU - Sedlackova, Lucia

AU - Kataura, Tetsushi

AU - Otten, Elsje G.

AU - Panda, Prashanta K.

AU - Lara-Reyna, Samuel

AU - Korsgen, Miriam E.

AU - Kauffman, Kevin J.

AU - Huerta-Uribe, Alejandro

AU - Zatyka, Malgorzata

AU - Silva, Luiz F.S.E.

AU - Torresi, Jorge

AU - Zhang, Shupei

AU - Hughes, Georgina W.

AU - Ward, Carl

AU - Kuechler, Erich R.

AU - Cartwright, David

AU - Trushin, Sergey

AU - Trushina, Eugenia

AU - Sahay, Gaurav

AU - Buganim, Yosef

AU - Lavery, Gareth G.

AU - Gsponer, Joerg

AU - Anderson, Daniel G.

AU - Frickel, Eva Maria

AU - Rosenstock, Tatiana R.

AU - Barrett, Timothy

AU - Maddocks, Oliver D.K.

AU - Tennant, Daniel A.

AU - Wang, Haoyi

AU - Jaenisch, Rudolf

AU - Korolchuk, Viktor I.

AU - Sarkar, Sovan

PY - 2023/5/30

Y1 - 2023/5/30

N2 - Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5−/− neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5−/− neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5−/− neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

AB - Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5−/−) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5−/− neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5−/− neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5−/− neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

KW - CP: Cell biology

KW - CP: Metabolism

KW - NAD

KW - NADases

KW - NAM

KW - NMN

KW - NR

KW - autophagy

KW - cell death

KW - cell survival, human embryonic stem cell-derived neurons

KW - mitochondria

KW - nicotinamide

KW - nicotinamide adenine dinucleotide

KW - nicotinamide mononucleotide

KW - nicotinamide riboside

UR - http://www.scopus.com/inward/record.url?scp=85152733124&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85152733124&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112372

DO - 10.1016/j.celrep.2023.112372

M3 - Article

C2 - 37086404

AN - SCOPUS:85152733124

SN - 2211-1247

VL - 42

JO - Cell reports

JF - Cell reports

IS - 5

M1 - 112372

ER -

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

Abstract

Keywords

ASJC Scopus subject areas

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