Lew, Sze Yuen and Hisam, Nur Shahirah Mohd and Phang, Michael Weng Lok and Syed Abdul Rahman, Syarifah Nur and Poh, Rozaida Yuen Ying and Lim, Siew Huah and Kamaruzzaman, Mohd Amir and Chau, Sze Chun and Tsui, Ka Chun and Lim, Lee Wei and Wong, Kah Hui (2023) Adenosine improves mitochondrial function and biogenesis in friedreich's ataxia fibroblasts following L-buthionine sulfoximine-induced oxidative stress. Biology-Basel, 12 (4). ISSN 2079-7737, DOI https://doi.org/10.3390/biology12040559.
Full text not available from this repository.Abstract
Simple Summary Friedreich's ataxia is the most common form of inherited ataxia, with an estimated prevalence of 1:50,000 in Caucasians. With no cure and a reduced lifespan, Friedreich's ataxia is a devastating neurodegenerative disease. At the present time, the treatment strategies are aimed at specific symptoms, such as supportive treatment and physical therapy for motor dysfunction. Medication could improve the symptoms. However, side effects may include intolerable nausea, insomnia, and/or depression. The lack of effective therapeutic options remains a major gap in the field. Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of Friedreich's ataxia. Here, we investigated the protective effects of adenosine against mitochondrial impairment in Friedreich's ataxia. We showed that adenosine attenuated the deleterious effects of oxidative stress and mitochondrial dysfunction by regulating mitochondrial function and biogenesis in fibroblasts derived from a Friedreich's ataxia patient. It serves as a promising therapeutic associated with mitochondrial dynamics that could eventually be a major breakthrough in the treatment of Friedreich's ataxia, ultimately improving the quality of life of Friedreich's ataxia patients and their caregivers and reducing its associated healthcare burden. Adenosine is a nucleoside that is widely distributed in the central nervous system and acts as a central excitatory and inhibitory neurotransmitter in the brain. The protective role of adenosine in different pathological conditions and neurodegenerative diseases is mainly mediated by adenosine receptors. However, its potential role in mitigating the deleterious effects of oxidative stress in Friedreich's ataxia (FRDA) remains poorly understood. We aimed to investigate the protective effects of adenosine against mitochondrial dysfunction and impaired mitochondrial biogenesis in L-buthionine sulfoximine (BSO)-induced oxidative stress in dermal fibroblasts derived from an FRDA patient. The FRDA fibroblasts were pre-treated with adenosine for 2 h, followed by 12.50 mM BSO to induce oxidative stress. Cells in medium without any treatments or pre-treated with 5 mu M idebenone served as the negative and positive controls, respectively. Cell viability, mitochondrial membrane potential (MMP), aconitase activity, adenosine triphosphate (ATP) level, mitochondrial biogenesis, and associated gene expressions were assessed. We observed disruption of mitochondrial function and biogenesis and alteration in gene expression patterns in BSO-treated FRDA fibroblasts. Pre-treatment with adenosine ranging from 0-600 mu M restored MMP, promoted ATP production and mitochondrial biogenesis, and modulated the expression of key metabolic genes, namely nuclear respiratory factor 1 (NRF1), transcription factor A, mitochondrial (TFAM), and NFE2-like bZIP transcription factor 2 (NFE2L2). Our study demonstrated that adenosine targeted mitochondrial defects in FRDA, contributing to improved mitochondrial function and biogenesis, leading to cellular iron homeostasis. Therefore, we suggest a possible therapeutic role for adenosine in FRDA.
| Item Type: | Article |
|---|---|
| Funders: | Ministry of Higher Education Malaysia via the Fundamental Research Grant Scheme (FRGS/1/2022/SKK06/UM/02/5), Ministry of Higher Education Malaysia via the Fundamental Research Grant Scheme (GPF003C-2019), RU Geran-Fakulti Program via University of Malaya Faculty of Medicine Research Grant (FRGS/1/2016/SKK06/UM/02/8), Universiti Malaya Page Charge Fund (PV036-2020) |
| Uncontrolled Keywords: | Adenosine; Friedreich's ataxia; Dermal fibroblasts; Oxidative stress; Mitochondrial function; Mitochondrial biogenesis |
| Subjects: | Q Science > QH Natural history > QH301 Biology |
| Divisions: | Faculty of Dentistry Faculty of Medicine Faculty of Science > Department of Chemistry |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 05 Jul 2023 08:16 |
| Last Modified: | 05 Jul 2023 08:16 |
| URI: | http://eprints.um.edu.my/id/eprint/38347 |
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