High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
复制标题
高脂肪饮食可改善 CHCHD10 突变小鼠的线粒体心肌病。
DOI：
10.1101/2023.02.22.529577
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Kawamata,Hibiki
中科院分区：
文献类型：
--
作者：
Southwell,Nneka;Manzo,Onorina;Zhao,Dazhi;Sayles,NicoleM;Dash,Jalia;Fujita,Keigo;D'Aurelio,Marilena;DiLorenzo,Annarita;Manfredi,Giovanni;Kawamata,Hibiki
chchd10是一种功能不明的线粒体蛋白，其突变与常染色体显性线粒体疾病有关。携带杂合S55L突变（相当于人类致病性S59L）的CHCHD10敲入小鼠会发生由CHCHD10聚集和蛋白质毒性线粒体综合应激反应（mtISR）引起的致命线粒体心肌病。在突变型心脏中，mtISR伴随着代谢重组，其特征是增加对糖酵解而不是脂肪酸氧化的依赖。为了对抗这种代谢重组，杂合子S55L小鼠接受慢性高脂肪饮食（HFD），以降低胰岛素敏感性和葡萄糖摄取，并增强心脏脂肪酸的利用。HFD改善了突变心脏的心室功能障碍，并显著延长了受严重妊娠性心肌病影响的突变雌性小鼠的存活率。基因表达谱证实，HFD增加了脂肪酸的利用，改善了心肌病标志物。重要的是，HFD还减少了S55L心脏中聚集的CHCHD10的积累，提示激活了质量控制机制。总之，我们的研究结果表明，代谢疗法对与蛋白质毒性应激相关的线粒体心肌病是有效的。
Mutations inCHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases.Chchd10knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high-fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.