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Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing
Published on: June 9, 2017
Selective impairment on the proliferation of neural progenitor cells by oxidative phosphorylation disruption
Yujeong Lee1, Shin Bi Oh, Hee Ra Park
1Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Longevity Life Science and Technology Institutes, Pusan National University, Geumjeong-gu, Busan 609-735, Republic of Korea.
Abstract:
Mitochondria produce ATP, regulate apoptosis, and maintain calcium homeostasis, and thus, mitochondrial dysfunction critically impairs nervous system development. Furthermore, the disruption of oxidative phosphorylation (OXPHOS) in mitochondria could lead to energy depletion and elevate oxidative stress. In the present study, the authors investigated how perturbation of the respiratory chain and bioenergetics affects neural progenitor cells (NPCs). Mitochondrial OXPHOS was impaired by inhibiting electron transfer using the antimycin A and ATP synthase inhibitor oligomycin. It was found that oligomycin impaired NPCs proliferation and was toxic at high concentrations, whereas antimycin A-treated cells showed no changes in NPCs proliferation. Although ROS production was elevated concentration-dependently by both inhibitors, oligomycin-treated C17.2 NPCs, but not antimycin A-treated NPCs, showed a significantly higher cell death rate and lower levels of intracellular ATP. These findings suggest that bioenergetic considerations are critically important for cell viability regulation in NPCs. Taken together, the present study shows that OXPHOS disruption can have a neurotoxic effect on NPCs, and thus, adversely influence the developing brain and the neurogenic capacity of the adult brain.
Insights
Mitochondrial dysfunction impairs neural progenitor cell (NPC) development. Inhibiting ATP synthase, but not electron transfer, reduced NPC proliferation and viability, highlighting bioenergetics
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondria are crucial for cellular energy production (ATP), apoptosis regulation, and calcium homeostasis.
- Mitochondrial dysfunction, particularly impaired oxidative phosphorylation (OXPHOS), can lead to energy deficits and increased oxidative stress, impacting nervous system development.
Purpose of the Study:
- To investigate the effects of disrupting mitochondrial oxidative phosphorylation (OXPHOS) on neural progenitor cells (NPCs).
- To determine how inhibiting specific components of the respiratory chain and ATP synthesis impacts NPC proliferation, viability, and energy status.
Main Methods:
- Neural progenitor cells (NPCs) were treated with antimycin A (electron transport inhibitor) and oligomycin (ATP synthase inhibitor) to impair mitochondrial OXPHOS.
- Cell proliferation, cell death rates, reactive oxygen species (ROS) production, and intracellular ATP levels were measured.
Main Results:
- Oligomycin treatment impaired NPC proliferation and exhibited toxicity at higher concentrations, unlike antimycin A.
- Both inhibitors increased ROS production in a dose-dependent manner.
- Oligomycin-treated NPCs showed significantly higher cell death and lower intracellular ATP levels compared to antimycin A-treated cells.
Conclusions:
- Disruption of mitochondrial bioenergetics, specifically ATP synthesis, has a significant neurotoxic effect on neural progenitor cells.
- Cellular energy status is critical for maintaining NPC viability and function.
- Impaired OXPHOS may adversely affect brain development and adult neurogenesis.
