Cell-Permeable Succinate Increases Mitochondrial Membrane Potential and Glycolysis in Leigh Syndrome Patient Fibroblasts.
Cell-Permeable Succinate Increases Mitochondrial Membrane Potential and Glycolysis in Leigh Syndrome Patient Fibroblasts.
复制标题
细胞渗透性琥珀酸盐增加Leigh综合征患者成纤维细胞的线粒体膜电位和糖酵解。
作者：
Bakare AB;Rao RR;Iyer S
线粒体疾病是一大类严重的遗传性疾病，主要影响能量需求高的器官系统。利氏综合征（LS）是线粒体疾病的典型例子，由致病性突变破坏氧化磷酸化能力。目前，针对LS的循证治疗方法很少。最近，负责调节电子传递链的细胞渗透底物作为线粒体疾病的治疗剂受到了关注。我们探讨了引入三羧酸循环（TCA）中间底物琥珀酸盐作为细胞渗透性前药NV118的治疗效果，以缓解LS的一些线粒体功能障碍。结果表明，前药NV118治疗24小时可引起LS细胞糖酵解和线粒体膜电位上调，同时抑制细胞内活性氧。本研究结果提示TCA中间体在治疗LS线粒体功能障碍中具有重要作用。我们在这里表明，NV118可以作为一种治疗剂，用于治疗由复合体I和复合体V功能障碍中mtDNA突变引起的LS。
Mitochondrial disorders represent a large group of severe genetic disorders mainly impacting organ systems with high energy requirements. Leigh syndrome (LS) is a classic example of a mitochondrial disorder resulting from pathogenic mutations that disrupt oxidative phosphorylation capacities. Currently, evidence-based therapy directed towards treating LS is sparse. Recently, the cell-permeant substrates responsible for regulating the electron transport chain have gained attention as therapeutic agents for mitochondrial diseases. We explored the therapeutic effects of introducing tricarboxylic acid cycle (TCA) intermediate substrate, succinate, as a cell-permeable prodrug NV118, to alleviate some of the mitochondrial dysfunction in LS. The results suggest that a 24-hour treatment with prodrug NV118 elicited an upregulation of glycolysis and mitochondrial membrane potential while inhibiting intracellular reactive oxygen species in LS cells. The results from this study suggest an important role for TCA intermediates for treating mitochondrial dysfunction in LS. We show, here, that NV118 could serve as a therapeutic agent for LS resulting from mutations in mtDNA in complex I and complex V dysfunctions.
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DOI：
10.3390/life11040288
发表时间：
2021-03-28
期刊：
Life (Basel, Switzerland)
影响因子：
--
作者：
Avram VF;Bîna AM;Sima A;Aburel OM;Sturza A;Burlacu O;Timar RZ;Muntean DM;Elmér E;Crețu OM
通讯作者：
Crețu OM
影响因子：
3.7
作者：
Hill BG;Benavides GA;Lancaster JR Jr;Ballinger S;Dell'Italia L;Jianhua Z;Darley-Usmar VM
通讯作者：
Darley-Usmar VM
影响因子：
4.8
作者：
Johnson, JD;Mehus, JG;Lambeth, DO
通讯作者：
Lambeth, DO
影响因子：
16.6
作者：
Ehinger JK;Piel S;Ford R;Karlsson M;Sjövall F;Frostner EÅ;Morota S;Taylor RW;Turnbull DM;Cornell C;Moss SJ;Metzsch C;Hansson MJ;Fliri H;Elmér E
通讯作者：
Elmér E
DOI：
10.1042/cs20140101
发表时间：
2014-09
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Chacko BK;Kramer PA;Ravi S;Benavides GA;Mitchell T;Dranka BP;Ferrick D;Singal AK;Ballinger SW;Bailey SM;Hardy RW;Zhang J;Zhi D;Darley-Usmar VM
通讯作者：
Darley-Usmar VM