Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Liao, X; Zhang, R; Lu, Y; Prosdocimo, DA; Sangwung, P; Zhang, L; Zhou, G; Anand, P; Lai, L; Leone, TC; Fujioka, H; Ye, F; Rosca, MG; Hoppel, CL; Schulze, PC; Abel, ED; Stamler, JS; Kelly, DP; Jain, MK

Published Date

  • September 2015

Published In

Volume / Issue

  • 125 / 9

Start / End Page

  • 3461 - 3476

PubMed ID

  • 26241060

Pubmed Central ID

  • 26241060

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI79964

Language

  • eng

Conference Location

  • United States