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

J Clin Invest. 2015 Sep;125(9):3461-76. doi: 10.1172/JCI79964. Epub 2015 Aug 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics
  • HEK293 Cells
  • Heart Diseases / genetics
  • Heart Diseases / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Oxygen Consumption / genetics
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Rats
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1