NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency
Congxin Sun, Elena Seranova, Malkiel A. Cohen, Miruna Chipara, Jennie Roberts, Dewi Astuti, Adina M. Palhegyi, Animesh Acharjee, Lucia Sedlackova, Tetsushi Kataura, Elsje G. Otten, Prashanta Kumar Panda, Samuel Lara‐Reyna, Miriam E. Korsgen, Kevin Kauffman, Alejandro Huerta Uribe, Malgorzata Zatyka, Luiz Silva, Jorge Torresi, Shupei Zhang, Georgina W. Hughes, Carl Ward, Erich R. Kuechler, David Cartwright, Sergey Trushin, Eugenia Trushina, Gaurav Sahay, Yosef Buganim, Gareth G. Lavery, Joerg Gsponer, Daniel G. Anderson, Eva‐Maria Frickel, Tatiana R. Rosenstock, Timothy Barrett, Oliver D.K. Maddocks, Daniel A. Tennant, Haoyi Wang, Rudolf Jaenisch, Viktor I. Korolchuk, Sovan Sarkar
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.