NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.
Sun, Congxin Seranova, Elena Cohen, Malkiel A Chipara, Miruna Roberts, Jennie Astuti, Dewi Palhegyi, Adina M Acharjee, Animesh Sedlackova, Lucia Kataura, Tetsushi
Sun, Congxin
Seranova, Elena
Cohen, Malkiel A
Chipara, Miruna
Roberts, Jennie
Astuti, Dewi
Palhegyi, Adina M
Acharjee, Animesh
Sedlackova, Lucia
Kataura, Tetsushi
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2023-04-21
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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.
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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 EM, Rosenstock TR, Barrett T, Maddocks ODK, Tennant DA, Wang H, Jaenisch R, Korolchuk VI, Sarkar S. NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency. Cell Rep. 2023 May 30;42(5):112372. doi: 10.1016/j.celrep.2023.112372. Epub 2023 Apr 21.
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