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 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 4

Myocardial KLF4 is required for postnatal mitochondrial biogenesis and cardiac maturation.

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Myocardial KLF4 is required for postnatal mitochondrial biogenesis and c...
(A) Expression of KLF4 and PPARGC1A in human and mouse hearts. Prenatal data were used as controls. n = 4 for each data point. (B) Heart size and weight. (C) Heart contractility, as assessed by echocardiography. (B and C) n = 5–7 at 4 weeks of age. (D) Myocardium ultrastructure. Representative images are shown (n = 3 in each group). Scale bar: 1 μm. (E) Cardiac mitochondrial genomic DNA, as assessed by qPCR. Mitochondrial genome copies (mtDNA) were normalized to nuclear DNA content. n = 10 in each genotype. Dots showed qPCR results from 5 pairs of primers (mt-Nd1, mt-Nd4, mt-Co1, mt-Co2, and mt-Atp6). (F) Expression of genes encoded by the mitochondrial genome. Ndufb5, a nuclear-encoded gene, was included as control. (G) Protein levels of mitochondrial- and nuclear-encoded genes. Each lane represents one animal. (H) Acute knockdown or (I) overexpression of KLF4 in NRVMs affected expression of mitochondrial-encoded genes. Cox5b, a nuclear-encoded gene, was included as control. (J) Deficiency of cardiac KLF4 impaired the expression of genes that regulate mitochondrial dynamics. Heart samples: n = 10. NRVM samples: n = 3. DNA/RNA/protein analysis was performed with 2-week-old animals. *P < 0.05, Student’s t test with Bonferroni correction.