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

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

doi:10.1172/JCI79964

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

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

Xudong Liao, Rongli Zhang, Yuan Lu, Domenick A Prosdocimo, Panjamaporn Sangwung, Lilei Zhang, Guangjin Zhou, Puneet Anand, Ling Lai, Teresa C Leone, …

The Journal of clinical investigation, Vol.125(9), pp.3461-3476

09/01/2015

DOI: 10.1172/JCI79964

PMCID: PMC4588311

PMID: 26241060

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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.

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Title: Subtitle: Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis
Creators: Xudong Liao - Case Cardiovascular Research Institute and
Rongli Zhang - Case Cardiovascular Research Institute and
Yuan Lu - Case Cardiovascular Research Institute and
Domenick A Prosdocimo - Case Cardiovascular Research Institute and
Panjamaporn Sangwung - Case Cardiovascular Research Institute and
Lilei Zhang - Case Cardiovascular Research Institute and
Guangjin Zhou - Case Cardiovascular Research Institute and
Puneet Anand - Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA
Ling Lai - Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
Teresa C Leone - Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
Hisashi Fujioka - Electron Microscopy Facility and
Fang Ye - Center for Mitochondrial Diseases, Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
Mariana G Rosca - Central Michigan University College of Medicine, Mount Pleasant, Michigan, USA
Charles L Hoppel - Center for Mitochondrial Diseases, Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
P. Christian Schulze - Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA
E. Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
Jonathan S Stamler - Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA
Daniel P Kelly - Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
Mukesh K Jain - Case Cardiovascular Research Institute and
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.125(9), pp.3461-3476
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI79964
PMID: 26241060
PMCID: PMC4588311
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 09/01/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024551902771

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