NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

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 ORCID: https://orcid.org/0000-0001-5794-748X, Gsponer, J, Anderson, DG, Frickel, E-M, Rosenstock, TR, Barrett, T, Maddocks, ODK, Tennant, DA, Wang, H, Jaenisch, R, Korolchuk, VI and Sarkar, S, 2023. NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency. Cell Reports, 42 (5): 112372. ISSN 2211-1247

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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.

Item Type:	Journal article
Publication Title:	Cell Reports
Creators:	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., Zhang, S., Hughes, G.W., Ward, C., Kuechler, E.R., Cartwright, D., Trushin, S., Trushina, E., Sahay, G., Buganim, Y., Lavery, G.G., Gsponer, J., Anderson, D.G., Frickel, E.-M., Rosenstock, T.R., Barrett, T., Maddocks, O.D.K., Tennant, D.A., Wang, H., Jaenisch, R., Korolchuk, V.I. and Sarkar, S.
Publisher:	Elsevier BV
Date:	30 May 2023
Volume:	42
Number:	5
ISSN:	2211-1247
Identifiers:	Number Type 10.1016/j.celrep.2023.112372 DOI 2554621 Other
Rights:	© 2023 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Divisions:	Schools > School of Science and Technology
Record created by:	Jeremy Silvester
Date Added:	09 Jan 2026 11:32
Last Modified:	09 Jan 2026 11:32
URI:	https://irep.ntu.ac.uk/id/eprint/55004

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