School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, VIC 3216, Australia.
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
Int J Mol Sci. 2022 Oct 20;23(20):12610. doi: 10.3390/ijms232012610.
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid β-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII/CIV and CI/CIII/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.
由于缺乏有效的线粒体疾病治疗方法，人们已经开发出了新的方法，包括刺激线粒体生物发生以提高 ATP 产生的方法。在这里，我们研究了脱氧核苷（dN）对短链烯酰基辅酶 A 水合酶 1（ECHS1）“敲除”（KO）细胞中线粒体生物发生和功能的影响，这些细胞同时表现出氧化磷酸化（OXPHOS）和线粒体脂肪酸β-氧化（FAO）的缺陷。dN 处理增加了线粒体 DNA（mtDNA）拷贝数和 mtDNA 编码转录物的表达，无论是在对照（CON）还是 ECHS1 KO 细胞中。dN 处理还改变了全核基因表达，关键基因集包括“呼吸电子传递”和“通过化学渗透偶联形成 ATP”在 CON 和 ECHS1 KO 细胞中均增加。dN 处理后，参与 OXPHOS 复合物 I 生物发生的基因在 CON 和 ECHS1 KO 细胞中也上调，ECHS1 KO 细胞中 holocomplex I 的稳态水平相应增加。dN 处理还增加了 ECHS1 KO 细胞中线粒体呼吸链酶复合物 V 的稳态水平，以及 CIII/CIV 和 CI/CIII/CIV 超复合物。重要的是，dN 处理增加了 ECHS1 KO 细胞在代谢葡萄糖或脂肪酸肉毒碱棕榈酰时的基础和最大线粒体耗氧量。这些发现强调了 dN 通过刺激线粒体生物发生来改善整体线粒体呼吸功能的能力，这是由于 ECHS1 缺乏导致 OXPHOS 和 FAO 联合缺陷的情况下。
