title: 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.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.forename: Panjamaporn
authors.initials: P
authors.lastname: Sangwung
authors.forename: Lilei
authors.initials: L
authors.lastname: Zhang
authors.forename: Guangjin
authors.initials: G
authors.lastname: Zhou
authors.forename: Puneet
authors.initials: P
authors.lastname: Anand
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.forename: Fang
authors.initials: F
authors.lastname: Ye
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Rosca
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D057809:HEK293 Cells; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1