The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation.
The mitochondrion of Plasmodium falciparum is required for cellular acetyl-CoA metabolism and protein acetylation.
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DOI：
10.1073/pnas.2210929120
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发表时间：
2023-04-25
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
血液阶段的疟疾寄生虫必须从人类宿主那里吸收营养脂肪酸才能生存。我们研究了线粒体蛋白质参与硫辛酸代谢的作用，以了解为什么硫辛酸是必需的。我们发现这些蛋白质参与乙酰辅酶A的产生，并且这种代谢产物用于细胞的不同隔室，包括用于核组蛋白的乙酰化。最终，基因表达等过程可能依赖于乙酰辅酶A的产生，从而在乙酰辅酶A与依赖乙酰辅酶A的广泛细胞现象之间建立了不寻常的联系。辅酶A（CoA）的生物合成是抗疟干预的一个很好的靶点。虽然大多数研究都集中在使用CoA在顶质体和疟疾寄生虫的胞质溶胶中产生乙酰辅酶A，但线粒体乙酰辅酶A的产生还不太清楚。在目前的研究中，我们进行了代谢物标记实验，以测量内源性代谢物在恶性疟原虫株系与影响线粒体脱氢酶活性的基因缺失。我们的研究结果表明，细胞乙酰辅酶A的生物合成所需的，并确定两个主要的酮酸脱氢酶之间的合成致死的关系。这些酶的活性依赖于硫辛酸附着酶LipL2，LipL2仅基于其在支持乙酰辅酶A代谢中的作用而对寄生虫存活至关重要。我们还发现，乙酰辅酶A中产生的乙酰辅酶A是必不可少的乙酰化组蛋白和其他蛋白质的乙酰化外的乙酰辅酶A。两者合计，我们的研究结果表明，所需的乙酰辅酶A代谢和蛋白质乙酰化寄生虫的生存。
Blood-stage malaria parasites must scavenge the nutrient lipoate from the human host in order to survive. We investigated the roles of mitochondrial proteins involved in lipoate metabolism to understand why lipoate is required in the mitochondrion. We found that these proteins are involved in the production of acetyl-CoA and that this metabolite is used in different compartments of the cell, including for the acetylation of nuclear histones. Ultimately, processes such as gene expression may rely on the production of acetyl-CoA, creating an unusual link between the mitochondrion and a broad range of cellular phenomena that rely on acetyl-CoA. Coenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in the apicoplast and the cytosol of malaria parasites, mitochondrial acetyl-CoA production is less well understood. In the current study, we performed metabolite-labeling experiments to measure endogenous metabolites in Plasmodium falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity. Our results show that the mitochondrion is required for cellular acetyl-CoA biosynthesis and identify a synthetic lethal relationship between the two main ketoacid dehydrogenase enzymes. The activity of these enzymes is dependent on the lipoate attachment enzyme LipL2, which is essential for parasite survival solely based on its role in supporting acetyl-CoA metabolism. We also find that acetyl-CoA produced in the mitochondrion is essential for the acetylation of histones and other proteins outside of the mitochondrion. Taken together, our results demonstrate that the mitochondrion is required for cellular acetyl-CoA metabolism and protein acetylation essential for parasite survival.
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影响因子：
9.9
作者：
Bryant, Jessica M.;Baumgarten, Sebastian;Scherf, Artur
通讯作者：
Scherf, Artur
影响因子：
3.2
作者：
Fletcher S;Lucantoni L;Sykes ML;Jones AJ;Holleran JP;Saliba KJ;Avery VM
通讯作者：
Avery VM
影响因子：
6.4
作者：
Jhun H;Walters MS;Prigge ST
通讯作者：
Prigge ST
影响因子：
4.6
作者：
Cobbold SA;Santos JM;Ochoa A;Perlman DH;Llinás M
通讯作者：
Llinás M
影响因子：
3.6
作者：
Foth, BJ;Stimmler, LM;McFadden, GI
通讯作者：
McFadden, GI