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NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

Lookup NU author(s): Lucy Sedlackova, Dr Tetsushi Kataura, Gisela Otten, Dr Viktor Korolchuk

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023 The Author(s)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.

Publication metadata

Author(s): 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 E-M, Rosenstock TR, Barrett T, Maddocks ODK, Tennant DA, Wang H, Jaenisch R, Korolchuk VI, Sarkar S

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2023

Volume: 42

Issue: 5

Print publication date: 30/05/2023

Online publication date: 21/04/2023

Acceptance date: 23/03/2023

Date deposited: 05/05/2023

ISSN (electronic): 2211-1247

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.celrep.2023.112372

DOI: 10.1016/j.celrep.2023.112372

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