IMR Press / FBL / Volume 27 / Issue 4 / DOI: 10.31083/j.fbl2704115
Open Access Original Research
Effects of Tolerance-Induced Preconditioning on Mitochondrial Biogenesis in Undifferentiated and Differentiated Neuronal Cells
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1 Translational Bioscience, Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada
2 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
3 Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, 50046 Changhua, Taiwan
4 Institute of Clinical Medicine, School of Medicine, National Yang Ming Chio Tung University, 11221 Taipei, Taiwan
5 Researcher Emeritus, Human Health Therapeutics Centre, National Research Council Canada, Ottawa, ON K1A 0R6, Canada
*Correspondence: (Jagdeep K. Sandhu); (Yau-Huei Wei)
Academic Editor: Josef Jampilek
Front. Biosci. (Landmark Ed) 2022, 27(4), 115;
Submitted: 18 January 2022 | Revised: 2 March 2022 | Accepted: 4 March 2022 | Published: 1 April 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Mitochondrial biogenesis occurs in response to chronic stresses as an adaptation to the increased energy demands and often renders cells more refractive to subsequent injuries which is referred to as preconditioning. This phenomenon is observed in several non-neuronal cell types, but it is not yet fully established in neurons, although it is fundamentally important for neuroprotection and could be exploited for therapeutic purposes. Methods: This study was designed to examine whether the preconditioning treatment with hypoxia or nitric oxide could trigger biogenesis in undifferentiated and differentiated neuronal cells (rat PC12 and human NT2 cells) as well as in primary mouse cortical neurons. Results: The results showed that both preconditioning paradigms induced mitochondrial biogenesis in undifferentiated cell lines, as indicated by an increase of mitochondrial mass (measured by flow cytometry of NAO fluorescence) and increased expression of genes required for mitochondrial biogenesis (Nrf1, Nrf2, Tfam, Nfκb1) and function (Cox3, Hk1). All these changes translated into an increase in the organelle copy number from an average of 20–40 to 40–60 mitochondria per cell. The preconditioning treatments also rendered the cells significantly less sensitive to the subsequent oxidative stress challenge brought about by oxygen/glucose deprivation, consistent with their improved cellular energy status. Mitochondrial biogenesis was abolished when preconditioning treatments were performed in the presence of antioxidants (vitamin E or CoQ10), indicating clearly that ROS-signaling pathway(s) played a critical role in the induction of this phenomenon in undifferentiated cells. However, mitochondrial biogenesis could not be re-initiated by preconditioning treatments in any of the post-mitotic neuronal cells tested, i.e., neither rat PC12 cells differentiated with NGF, human NT2 cells differentiated with retinoic acid nor mouse primary cortical neurons. Instead, differentiated neurons had a much higher organelle copy number per cell than their undifferentiated counterparts (100–130 mitochondria per neuron vs. 20–40 in proliferating cells), and this feature was not altered by preconditioning. Conclusions: Our study demonstrates that mitochondrial biogenesis occurred during the differentiation process resulting in more beneficial energy status and improved tolerance to oxidative stress in neurons, putting in doubt whether additional enhancement of this phenomenon could be achieved and successfully exploited as a way for better neuroprotection.

oxidative stress
rat PC12 cells
human NT2 cells
coenzyme Q10
Fig. 1.
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