Altered Mitochondrial Function and Accelerated Aging Phenotype in Neural Stem Cells Derived from Dnm1l Knockout Embryonic Stem Cells

• Published in: International journal of molecular sciences 2023-09, Vol.24 (18), p.14291
• Main Authors: Na, Seung-Bin, Seo, Bong-Jong, Hong, Tae-Kyung, Oh, Seung-Yeon, Hong, Yean-Ju, Song, Jae-Hoon, Uhm, Sang-Jun, Hong, Kwonho, Do, Jeong-Tae
• Format: Article
• Language: English
• Subjects: Aging; Cell death; Dnm1l; Embryonic stem cells; Energy; energy metabolism; Epidermal growth factor; Genetic aspects; Metabolism; Mitochondria; Morphology; neural stem cells; Neurogenesis; Physiological aspects; Stem cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241814291

Mitochondria are crucial for cellular energy metabolism and are involved in signaling, aging, and cell death. They undergo dynamic changes through fusion and fission to adapt to different cellular states. In this study, we investigated the effect of knocking out the dynamin 1-like protein (Dnm1l) gene, a key regulator of mitochondrial fission, in neural stem cells (NSCs) differentiated from Dnm1l knockout embryonic stem cells (Dnm1l−/− ESCs). Dnm1l−/− ESC-derived NSCs (Dnm1l−/− NSCs) exhibited similar morphology and NSC marker expression (Sox2, Nestin, and Pax6) to brain-derived NSCs, but lower Nestin and Pax6 expression than both wild-type ESC-derived NSCs (WT-NSCs) and brain-derived NSCs. In addition, compared with WT-NSCs, Dnm1l−/− NSCs exhibited distinct mitochondrial morphology and function, contained more elongated mitochondria, showed reduced mitochondrial respiratory capacity, and showed a metabolic shift toward glycolysis for ATP production. Notably, Dnm1l−/− NSCs exhibited impaired self-renewal ability and accelerated cellular aging during prolonged culture, resulting in decreased proliferation and cell death. Furthermore, Dnm1l−/− NSCs showed elevated levels of inflammation and cell stress markers, suggesting a connection between Dnm1l deficiency and premature aging in NSCs. Therefore, the compromised self-renewal ability and accelerated cellular aging of Dnm1l−/− NSCs may be attributed to mitochondrial fission defects.