NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency
Name
1-s2.0-S2211124723003832-main.pdf
Description
Published version
Size
8.23 MB
Format
Adobe PDF
Checksum (MD5)
4030a9ac291e8ddc25eda2aeaf0ff50a
Date Issued
May 2023
Journal
Cell Reports
Publisher
Elsevier BV
Citation
2023. "NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency." Cell Reports, 42 (5).
Version
Final published version
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.
MIT Department
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.celrep.2023.112372
