Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis
Xudong Liao, … , Daniel P. Kelly, Mukesh K. Jain
Xudong Liao, … , Daniel P. Kelly, Mukesh K. Jain
Published September 1, 2015; First published August 4, 2015
Citation Information: J Clin Invest. 2015;125(9):3461-3476. https://doi.org/10.1172/JCI79964.
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Research Article Cardiology

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

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.

Authors

Xudong Liao, Rongli Zhang, Yuan Lu, Domenick A. Prosdocimo, Panjamaporn Sangwung, Lilei Zhang, Guangjin Zhou, Puneet Anand, Ling Lai, Teresa C. Leone, Hisashi Fujioka, Fang Ye, Mariana G. Rosca, Charles L. Hoppel, P. Christian Schulze, E. Dale Abel, Jonathan S. Stamler, Daniel P. Kelly, Mukesh K. Jain

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Figure 1

KLF4 is required for the bioenergetic and functional adaptation to cardiac pressure overload.

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KLF4 is required for the bioenergetic and functional adaptation to cardi...
(A) LV function, heart weight (HW), lung weight (LW), and expression of hypertrophic marker genes in the heart. BW, body weight. (B) Microarray analysis. Heat map showing marginal differences in sham groups but dramatic differences in TAC groups between A-Cre and A-cKO mice. Genes that were differentially expressed in TAC groups (fold change over 1.5, A-cKO vs. A-Cre mice) were subjected to gene enrichment analysis. ES, enrichment score. (C) qPCR analysis of some cardiac metabolic and mitochondrial genes. n = 4 for sham groups, n = 7 for A-Cre TAC group, n = 5 for A-cKO TAC group. (D) Myocardial ATP levels. (E) Myocardial ROS levels, as assessed by DHE staining. Scale bar: 20 μm. (F) Myocardium ultrastructure, as assessed by transmission electron microscopy (TEM), showing mitochondrial damage after TAC. Scale bar: 2 μm. Representative images (n = 3) are shown. Measurements were taken 3 days after sham and TAC operations. #P < 0.05 between sham groups; *P < 0.05 between TAC groups, Student’s t test with Bonferroni correction.