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

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

doi:10.1172/jci79964

Cited by 105 publications

(114 citation statements)

References 69 publications

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“…For example, reduction of myocardial Klf4 increases susceptibility to heart failure (Liao et al, 2010), which mechanistically might be due to a loss of transcriptional control of mitochondrial biogenesis (Liao et al, 2015). Furthermore, the loss of Klf15 in mice increases susceptibility to heart failure and aortic aneurysmal formation in a p53-and p300 acetyltransferase-dependent manner .…”

Section: Klfs In Hematopoietic Disordersmentioning

confidence: 99%

Krüppel-like factors in mammalian stem cells and development

2017

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Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that are found in many species. Recent studies have shown that KLFs play a fundamental role in regulating diverse biological processes such as cell proliferation, differentiation, development and regeneration. Of note, several KLFs are also crucial for maintaining pluripotency and, hence, have been linked to reprogramming and regenerative medicine approaches. Here, we review the crucial functions of KLFs in mammalian embryogenesis, stem cell biology and regeneration, as revealed by studies of animal models. We also highlight how KLFs have been implicated in human diseases and outline potential avenues for future research.

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Section: Klfs In Hematopoietic Disordersmentioning

confidence: 99%

Krüppel-like factors in mammalian stem cells and development

2017

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“…ERRα also directly activates PPARα expression, providing a feed-forward mechanism to promote fatty acid and oxidative metabolism (47). Interestingly, the transcription factor KLF4 has recently been shown to bind in close proximity to ERR binding sites, including on the Ppara promoter (49). KLF4 synergizes with ERRα to activate target genes and is necessary for normal mitochondrial biogenesis and function in the heart (49).…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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Section: Introductionmentioning

confidence: 99%

“…Members of the KLF family play important roles in multiple cell types within the cardiovascular system [15–20]. In particular, our recent studies have identified Kruppel-like factor 4 (KLF4) as a critical regulator of cardiac mitochondrial homeostasis [20]. We previously showed that mice bearing cardiac deficiency of KLF4 were sensitized to pressure overload-induced heart failure due to disruption of mitochondrial homeostasis upon stress [18,20].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, our recent studies have identified Kruppel-like factor 4 (KLF4) as a critical regulator of cardiac mitochondrial homeostasis [20]. We previously showed that mice bearing cardiac deficiency of KLF4 were sensitized to pressure overload-induced heart failure due to disruption of mitochondrial homeostasis upon stress [18,20]. However, the underlying initial defects leading to such rapid cardiac dysfunction remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure

Zhang

Shen

Zhou

et al. 2017

Journal of Molecular and Cellular Cardiology

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Heart failure is associated with mitochondrial dysfunction so that restoring or improving mitochondrial health is of therapeutic importance. Recently, reduction in NAD+ levels and NAD+-mediated deacetylase activity has been recognized as negative regulators of mitochondrial function. Using a cardiac specific KLF4 deficient mouse line that is sensitive to stress, we found mitochondrial protein hyperacetylation coupled with reduced Sirt3 and NAD+ levels in the heart before stress, suggesting that the KLF4-deficient heart is predisposed to NAD+-associated defects. Further, we demonstrated that short-term administration of Nicotinamide Mononucleotide (NMN) successfully protected the mutant mice from pressure overload-induced heart failure. Mechanically, we showed that NMN preserved mitochondrial ultrastructure, reduced ROS and prevented cell death in the heart. In cultured cardiomyocytes, NMN treatment significantly increased long-chain fatty acid oxidation despite no direct effect on pyruvate oxidation. Collectively, these results provide cogent evidence that hyperacetylation of mitochondrial proteins is critical in the pathogenesis of cardiac disease and that administration of NMN may serve as a promising therapy.

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

Cited by 105 publications

References 69 publications

Krüppel-like factors in mammalian stem cells and development

Krüppel-like factors in mammalian stem cells and development

Cardiac nuclear receptors: architects of mitochondrial structure and function

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure

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