Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells.
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DOI：
10.1016/j.celrep.2022.111744
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发表时间：
2022-11-29
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
线粒体功能障碍是衰老的标志，与衰老表型和年龄相关疾病的发生有关。在这里，我们报告说，受损的线粒体功能与衰老的人间充质干细胞（MSC）和肌成纤维细胞来源于患有Hutchinson-Gilford早衰综合征的患者谷氨酰胺catalysts增加。转氨酶（GLS 1）活性增加伴随着尿素转运蛋白SLC 14 A1的丧失诱导尿素积累，线粒体功能障碍和DNA损伤。相反，阻断GLS 1活性可以恢复线粒体功能，并改善衰老标志。有趣的是，GLS 1表达通过JNK途径调节，如化学和遗传抑制所示。与我们的体外研究结果一致，从老年或早衰小鼠分离的组织显示尿素积累和GLS 1活性增加，伴随着线粒体功能下降。在早衰小鼠中抑制β-内酰胺酶解可改善线粒体呼吸链活性，这表明靶向β-内酰胺酶解可能是恢复与年龄相关的线粒体功能丧失的一种有前景的策略。Choudhury等人报道衰老细胞表现出增强的氨解和尿素转运蛋白的损失，增加尿素的产生和积累。细胞内尿素增加严重损害线粒体功能，并加剧衰老表型。通过阻断GLS 1来抑制多巴胺的分解，可以显著改善衰老细胞和早衰小鼠的线粒体功能。
Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired mitochondrial function is associated with increased glutamine catabolism in senescent human mesenchymal stem cells (MSCs) and myofibroblasts derived from patients suffering from Hutchinson-Gilford progeria syndrome. Increased glutaminase (GLS1) activity accompanied by loss of urea transporter SLC14A1 induces urea accumulation, mitochondrial dysfunction, and DNA damage. Conversely, blocking GLS1 activity restores mitochondrial function and leads to amelioration of aging hallmarks. Interestingly, GLS1 expression is regulated through the JNK pathway, as demonstrated by chemical and genetic inhibition. In agreement with our in vitro findings, tissues isolated from aged or progeria mice display increased urea accumulation and GLS1 activity, concomitant with declined mitochondrial function. Inhibition of glutaminolysis in progeria mice improves mitochondrial respiratory chain activity, suggesting that targeting glutaminolysis may be a promising strategy for restoring age-associated loss of mitochondrial function. Choudhury et al. report that senescent cells exhibit enhanced glutaminolysis and loss of urea transporter, increasing urea production and accumulation. Increased intracellular urea severely impairs mitochondrial function and exacerbates the aging phenotype. Inhibiting glutaminolysis by blocking GLS1 significantly improves mitochondrial function in senescent cells and progeria mice.
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影响因子：
64.8
作者：
Lee JE;Westrate LM;Wu H;Page C;Voeltz GK
通讯作者：
Voeltz GK
影响因子：
6
作者：
通讯作者：
--
DOI：
10.1007/s00018-021-03980-x
发表时间：
2021-12
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Deryabin PI;Shatrova AN;Borodkina AV
通讯作者：
Borodkina AV
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF
影响因子：
2.8
作者：
Gong Z;Muzumdar RH
通讯作者：
Muzumdar RH