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NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency

ABSTRACT: Metabolic profiling in wild type and autophagy-deficient human embryonic stem cell (hESC)-derived neurons after 3 weeks of neuronal differentiation. Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in myriad human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here we have generated autophagy-deficient human embryonic stem cells (hESCs), from which we have established human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5 deficient 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 depolarisation in ATG5 deficient neurons. Boosting intracellular NAD levels improve cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5 deficient 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.

INSTRUMENT(S): Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Sovan Sarkar

PROVIDER: MSV000091468 | MassIVE | Fri Mar 10 09:00:00 GMT 2023

REPOSITORIES: MassIVE

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