Modes of metabolic compensation during mitochondrial disease using the Drosophila model of ATP6 dysfunction.
Modes of metabolic compensation during mitochondrial disease using the Drosophila model of ATP6 dysfunction.
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DOI：
10.1371/journal.pone.0025823
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Palladino MJ
中科院分区：
文献类型：
--
作者：
Celotto AM;Chiu WK;Van Voorhies W;Palladino MJ
许多线粒体DNA突变导致线粒体脑肌病：目前尚无有效治疗方法的相关疾病的集合。线粒体脑肌病是一种复杂的多系统疾病，其严重程度不断恶化，使其难以治疗和研究。与慢性线粒体功能障碍相关的致病性和代偿性代谢变化尚不清楚。果蝇ATP61突变体模拟人类线粒体脑肌病，并允许研究受影响动物一生中发生的代谢变化和代偿。atp61动物在无症状时几乎完全丧失ATP合成酶活性和急性生物能量缺陷，但令人惊讶的是，我们发现这些动物在症状期没有慢性生物能量缺陷。我们的数据表明，尽管线粒体DNA内源性突变导致慢性线粒体复合体V功能障碍，动态代谢补偿机制仍能维持正常的能量可用性和活性。atp61动物在发病早期通过糖酵解通量、生酮和Kreb循环活性的增加来补偿氧化磷酸化的损失。然而，琥珀酸脱氢酶活性降低，线粒体超复合体的形成严重中断，导致了ATP61动物的发病机制。这些研究证明了代谢代偿机制的动态性，并强调需要在易驯化的动物系统中进行时间过程研究，以阐明疾病的发病机制和新的治疗途径。
Numerous mitochondrial DNA mutations cause mitochondrial encephalomyopathy: a collection of related diseases for which there exists no effective treatment. Mitochondrial encephalomyopathies are complex multisystem diseases that exhibit a relentless progression of severity, making them both difficult to treat and study. The pathogenic and compensatory metabolic changes that are associated with chronic mitochondrial dysfunction are not well understood. The Drosophila ATP61 mutant models human mitochondrial encephalomyopathy and allows the study of metabolic changes and compensation that occur throughout the lifetime of an affected animal. ATP61animals have a nearly complete loss of ATP synthase activity and an acute bioenergetic deficit when they are asymptomatic, but surprisingly we discovered no chronic bioenergetic deficit in these animals during their symptomatic period. Our data demonstrate dynamic metabolic compensatory mechanisms that sustain normal energy availability and activity despite chronic mitochondrial complex V dysfunction resulting from an endogenous mutation in the mitochondrial DNA. ATP61animals compensate for their loss of oxidative phosphorylation through increases in glycolytic flux, ketogenesis and Kreb's cycle activity early during pathogenesis. However, succinate dehydrogenase activity is reduced and mitochondrial supercomplex formation is severely disrupted contributing to the pathogenesis seen in ATP61 animals. These studies demonstrate the dynamic nature of metabolic compensatory mechanisms and emphasize the need for time course studies in tractable animal systems to elucidate disease pathogenesis and novel therapeutic avenues.
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影响因子：
3.5
作者：
D'Aurelio, M.;Vives-Bauza, C.;Manfredi, G.
通讯作者：
Manfredi, G.
影响因子：
--
作者：
Carelli, V;Baracca, A;Solaini, G
通讯作者：
Solaini, G
影响因子：
2
作者：
Debray, Francois-Guillaume;Lambert, Marie;Mitchell, Grant A.
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Mitchell, Grant A.
影响因子：
5.3
作者：
Ashmore, Lesley J.;Hrizo, Stacy L.;Palladino, Michael J.
通讯作者：
Palladino, Michael J.
影响因子：
2.9
作者：
Forester, Brent P.;Berlow, Yosef A.;Cohen, Bruce M.
通讯作者：
Cohen, Bruce M.