Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.
Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.
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DOI：
10.1016/j.celrep.2022.110475
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发表时间：
2022-03-08
期刊：
影响因子：
8.8
通讯作者：
Manfredi, Giovanni
中科院分区：
文献类型：
--
作者：
Sayles, Nicole M.;Southwell, Nneka;McAvoy, Kevin;Kim, Kihwan;Pesini, Alba;Anderson, Corey J.;Quinzii, Catarina;Cloonan, Suzanne;Kawamata, Hibiki;Manfredi, Giovanni
线粒体心肌病是致命的疾病，没有有效的治疗方法。心脏线粒体功能的改变会激活线粒体综合应激反应（ISRmt），这是一种影响细胞代谢、线粒体生物发生和蛋白质稳态的转录程序。在人类中，CHCHD10（一种功能未知的线粒体蛋白）的突变最近与显性多系统线粒体疾病相关，其致病机制仍有待阐明。在这里，在 CHCHD10 敲入突变小鼠中，我们发现了由蛋白毒性 ISRmt 触发的广泛心脏代谢重新布线。应激反应在生物能损伤发生之前就很早就出现，引发从氧化代谢向糖酵解代谢的转变、转硫作用和一碳 (1C) 代谢的增强以及广泛的代谢失衡。与此同时，NADPH 氧化酶的增加会引发抗氧化反应，导致血红素消耗。随着疾病的进展，适应性代谢应激反应失败，导致致命的心肌病。我们的研究结果表明，对抗代谢失衡的早期干预措施可以改善与蛋白毒性 ISRmt 相关的线粒体心肌病。塞尔斯等人。报告指出，突变型 CHCHD10 蛋白毒性可激活线粒体心肌病小鼠模型中的线粒体整合应激反应 (ISRmt)。慢性 ISRmt 会导致严重的代谢失衡，最终导致氧化应激和铁失调，最终导致线粒体功能障碍并导致疾病发病机制。
Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt. Sayles et al. report that mutant CHCHD10 proteotoxicity activates the mitochondrial integrated stress response (ISRmt) in a mouse model of mitochondrial cardiomyopathy. Chronic ISRmt causes profound metabolic imbalances, culminating in oxidative stress and iron dysregulation, ultimately resulting in mitochondrial dysfunction and contributing to disease pathogenesis.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
82.9
作者：
Cloonan SM;Glass K;Laucho-Contreras ME;Bhashyam AR;Cervo M;Pabón MA;Konrad C;Polverino F;Siempos II;Perez E;Mizumura K;Ghosh MC;Parameswaran H;Williams NC;Rooney KT;Chen ZH;Goldklang MP;Yuan GC;Moore SC;Demeo DL;Rouault TA;D'Armiento JM;Schon EA;Manfredi G;Quackenbush J;Mahmood A;Silverman EK;Owen CA;Choi AM
通讯作者：
Choi AM
影响因子：
--
作者：
Gammella E;Recalcati S;Rybinska I;Buratti P;Cairo G
通讯作者：
Cairo G
影响因子：
4.1
作者：
Fornuskova, Daniela;Stiburek, Lukas;Zeman, Jiri
通讯作者：
Zeman, Jiri
影响因子：
11.8
作者：
Higuchi-Sanabria R;Frankino PA;Paul JW 3rd;Tronnes SU;Dillin A
通讯作者：
Dillin A