Combinatorial glucose, nicotinic acid and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease.
Combinatorial glucose, nicotinic acid and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease.
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DOI：
10.1093/hmg/ddab059
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发表时间：
2021-05-12
影响因子：
3.5
通讯作者：
Falk MJ
中科院分区：
文献类型：
--
作者：
Guha S;Mathew ND;Konkwo C;Ostrovsky J;Kwon YJ;Polyak E;Seiler C;Bennett M;Xiao R;Zhang Z;Nakamaru-Ogiso E;Falk MJ
线粒体呼吸链疾病可通过多种抗氧化剂、辅因子和维生素“混合物”进行经验性治疗。然而，不存在用于任何单一或组合线粒体疾病治疗的经临床试验验证和批准的化合物或剂量。在这里，我们试图在临床前评估合理设计的线粒体药物组合方案是否可以协同改善呼吸链复合物 I 疾病的转化动物模型的生存、健康和生理学。之前已经证明，gas-1(fc21) 复合物 I 亚基 ndufs2−/− 线虫的寿命很短，可以用 17 种不同的代谢调节剂、信号调节剂或抗氧化剂来显着挽救，在这里，我们评估了这三种治疗类别的 11 种随机组合对 Gas-1(fc21) 寿命的影响。仅用葡萄糖、烟酸和 N-乙酰半胱氨酸 (Glu + NA + NAC) 进行协同救援，提高线粒体膜电位，反映综合呼吸链功能，不会加剧氧化应激，同时减少线粒体应激 (UPRmt) 并改善转录组水平的中间代谢破坏，稳态 代谢物和中间代谢通量。在基于鱼藤酮的复合物 I 抑制的斑马鱼脊椎动物模型中，等摩尔 Glu + NA + NAC 剂量可协同挽救幼虫活性、脑死亡、乳酸、ATP 和谷胱甘肽水平。总体而言，这些数据为线粒体复合物 I 疾病的两种进化差异动物模型提供了客观的临床前证据，证明组合 Glu + NA + NAC 疗法可显着提高动物的恢复能力，即使面对导致严重代谢缺陷的应激源，从而防止急性神经和生化失代偿。有必要进行临床试验来评估这种主要组合治疗方案的功效，以改善患有线粒体疾病的人类受试者的恢复能力和健康结果。
Mitochondrial respiratory chain disorders are empirically managed with variable antioxidant, cofactor and vitamin ‘cocktails’. However, clinical trial validated and approved compounds, or doses, do not exist for any single or combinatorial mitochondrial disease therapy. Here, we sought to pre-clinically evaluate whether rationally designed mitochondrial medicine combinatorial regimens might synergistically improve survival, health and physiology in translational animal models of respiratory chain complex I disease. Having previously demonstrated that gas-1(fc21) complex I subunit ndufs2−/− C. elegans have short lifespan that can be significantly rescued with 17 different metabolic modifiers, signaling modifiers or antioxidants, here we evaluated 11 random combinations of these three treatment classes on gas-1(fc21) lifespan. Synergistic rescue occurred only with glucose, nicotinic acid and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential that reflects integrated respiratory chain function, without exacerbating oxidative stress, and while reducing mitochondrial stress (UPRmt) and improving intermediary metabolic disruptions at the levels of the transcriptome, steady-state metabolites and intermediary metabolic flux. Equimolar Glu + NA + NAC dosing in a zebrafish vertebrate model of rotenone-based complex I inhibition synergistically rescued larval activity, brain death, lactate, ATP and glutathione levels. Overall, these data provide objective preclinical evidence in two evolutionary-divergent animal models of mitochondrial complex I disease to demonstrate that combinatorial Glu + NA + NAC therapy significantly improved animal resiliency, even in the face of stressors that cause severe metabolic deficiency, thereby preventing acute neurologic and biochemical decompensation. Clinical trials are warranted to evaluate the efficacy of this lead combinatorial therapy regimen to improve resiliency and health outcomes in human subjects with mitochondrial disease.
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影响因子：
9.3
作者：
Debray, Francois-Guillaume;Mitchell, Grant A.;Lambert, Marie
通讯作者：
Lambert, Marie
金黄色葡萄球菌对中央代谢物丙酮酸反应以调节毒力。
影响因子：
6.4
作者：
Harper L;Balasubramanian D;Ohneck EA;Sause WE;Chapman J;Mejia-Sosa B;Lhakhang T;Heguy A;Tsirigos A;Ueberheide B;Boyd JM;Lun DS;Torres VJ
通讯作者：
Torres VJ
影响因子：
3.6
作者：
Barcelos I;Shadiack E;Ganetzky RD;Falk MJ
通讯作者：
Falk MJ
影响因子：
10.5
作者：
Hamilton, B;Doug, YQ;Lee, SS
通讯作者：
Lee, SS
影响因子：
11.8
作者：
Haynes, Cole M.;Petrova, Kseniya;Ron, David
通讯作者：
Ron, David