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

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) ge...

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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
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241814291