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 intrac

SUBMITTER: Sun C 

PROVIDER: S-EPMC10556436 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature