Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation.
Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation.
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DOI：
10.1371/journal.pbio.2005707
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发表时间：
2018-04
期刊：
影响因子：
9.8
通讯作者：
Santos JH
中科院分区：
文献类型：
--
作者：
Lozoya OA;Martinez-Reyes I;Wang T;Grenet D;Bushel P;Li J;Chandel N;Woychik RP;Santos JH
线粒体功能影响细胞生理学的许多方面，最近，它在表观遗传学中的作用已被报道。从机制上讲，线粒体功能如何改变细胞核中的DNA甲基化模式仍然不清楚。利用诱导线粒体DNA （mtDNA）耗竭的细胞培养模型，本研究表明，进行性线粒体功能障碍导致以各种氨基酸代谢为中心的早期转录和代谢程序，包括那些参与蛋氨酸循环的氨基酸。我们发现这个程序也增加了DNA甲基化，这主要发生在差异表达的基因中。在mtDNA丢失的情况下，维持线粒体烟酰胺腺嘌呤二核苷酸还原（NADH）氧化可以挽救蛋氨酸和多胺合成，防止DNA甲基化和基因表达的变化，但不影响丝氨酸/叶酸代谢或转硫。这项工作提供了线粒体功能与基因表达表观遗传调控之间的新机制联系，涉及多胺和蛋氨酸代谢对三羧酸（TCA）循环变化的响应。鉴于这些发现的意义，未来的研究跨越不同的生理背景和体内是必要的。细胞核的表观遗传变化在基因表达调控中起作用，代谢已被证明影响表观基因组。线粒体不仅是细胞的动力源，也是重要的代谢中枢，线粒体代谢的变化可能会影响表观基因组，从而影响基因的表达。然而，线粒体功能是否会影响表观遗传学，以及这种影响是否会改变基因表达，目前尚不清楚。在这项工作中，我们使用线粒体功能被遗传操纵的细胞培养系统，同时研究对代谢、表观基因组和基因表达的影响。这种方法表明，线粒体呼吸的丧失导致了细胞范围内的代谢重新布线，主要以氨基酸为中心，通过影响蛋氨酸和多胺代谢来改变细胞核中的DNA甲基化。我们发现这些变化优先发生在响应线粒体功能障碍的基因中。最值得注意的是，所有这些影响都可以通过维持线粒体中烟酰胺腺嘌呤二核苷酸还原（NADH）氧化来逆转，揭示了这些细胞器和DNA甲基化之间的新联系。鉴于线粒体在许多疾病条件下的参与，这项工作为理解和潜在地操纵线粒体在健康和疾病中的功能开辟了新的挑战和机遇。
Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted. Epigenetic changes in the nucleus play a role in the regulation of gene expression, and metabolism has been shown to affect the epigenome. As mitochondria are not only the powerhouses but also important metabolic hubs in cells, changes in mitochondrial metabolism are likely to affect the epigenome and, as such, gene expression. However, it remains unclear whether mitochondrial function can affect epigenetics, and if such effects alter gene expression. In this work, we used cell culture systems in which mitochondrial function was genetically manipulated to simultaneously study the effects on metabolism, the epigenome, and gene expression. Such approach revealed that loss of mitochondrial respiration leads to a cell-wide metabolic rewiring primarily centered on amino acids, which altered DNA methylation in the nucleus by affecting methionine and polyamine metabolism. We found that these changes preferentially occur in genes responding to mitochondrial dysfunction. Most notably, all these effects could be reversed by maintaining nicotinamide adenine dinucleotide reduced (NADH) oxidation in the mitochondria, revealing a novel link between these organelles and DNA methylation. Given the involvement of mitochondria in many disease conditions, this work opens new challenges and opportunities to understand and potentially manipulate mitochondrial function in health and disease.
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SIRT3在饮食限制期间促进尿素周期和脂肪酸氧化。
影响因子：
16
作者：
Hallows WC;Yu W;Smith BC;Devries MK;Ellinger JJ;Someya S;Shortreed MR;Prolla T;Markley JL;Smith LM;Zhao S;Guan KL;Denu JM
通讯作者：
Denu JM
影响因子：
29
作者：
Ducker GS;Chen L;Morscher RJ;Ghergurovich JM;Esposito M;Teng X;Kang Y;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
4
作者：
Fan, Jing;Krautkramer, Kimberly A.;Feldman, Jessica L.;Denu, John M.
通讯作者：
Denu, John M.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1073/pnas.78.2.1219
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
KAMATANI, N;NELSONREES, WA;CARSON, DA
通讯作者：
CARSON, DA