Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cell Rep. 2023 May 30;42(5):112372. doi: 10.1016/j.celrep.2023.112372. Epub 2023 Apr 21.
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.
自噬是细胞生存的关键的一种自稳过程，其功能障碍与包括神经退行性疾病在内的人类疾病有关。自噬的丧失导致细胞毒性和组织退化，但对这一现象的机制理解仍难以捉摸。在这里，我们生成了自噬缺陷（ATG5）的人类胚胎干细胞（hESCs），并从中建立了一个人类神经元平台，以研究自噬的丧失如何影响神经元的存活。ATG5 神经元表现出基础细胞毒性，并伴有代谢缺陷。由于 NAD 消耗酶的过度激活导致烟酰胺腺嘌呤二核苷酸（NAD）耗竭，发现通过线粒体去极化触发 ATG5 神经元中的细胞死亡。通过恢复 ATG5 神经元中线粒体生物能和蛋白质稳态，提高细胞内 NAD 水平可改善细胞活力。我们的研究结果阐明了自噬缺陷与神经元细胞死亡之间的机制联系，这可能成为与自噬缺陷相关的神经退行性疾病和溶酶体贮积症的治疗干预的靶点。
