线粒体生物发生
KLF4公司
线粒体
生物
自噬
细胞生物学
转录因子
线粒体融合
DNAJA3公司
转录调控
内分泌学
线粒体DNA
遗传学
基因
细胞凋亡
SOX2
作者
Xudong Liao,Rongli Zhang,Yuan Lu,Domenick A. Prosdocimo,Panjamaporn Sangwung,Lilei Zhang,Guangjin Zhou,Puneet Anand,Ling‐Ping Lai,Teresa C. Leone,Hisashi Fujioka,Fang Ye,M. Rosca,Charles L. Hoppel,P. Christian Schulze,E. Dale Abel,Jonathan S. Stamler,Daniel P. Kelly,Mukesh K. Jain
摘要
Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac-specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARγ coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis.
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