While all cells in the body rely on metabolic pathways that take place within the mitochondria, the cells of some organs, such as the brain and heart, have an essential demand for constant energy. Maintaining the proper mitochondrial homeostasis is critical for overall tissue health, as defective mitochondria have been linked to a number of disease states.

Now, researchers at Case Western Reserve University have discovered that a protein called Kruppel-like Factor 4 (KLF4) is pivotal in catalyzing energy production within mitochondria. Specifically, they saw that the absence of KLF4 led to reduced energy production—a phenotype that is particularly problematic for cardiac cells.

“Some cells are incredibly dependent on mitochondria, particularly the heart and brain,” explained lead author Xudong Liao, Ph.D., an assistant professor of medicine at Case Western Reserve University School of Medicine. “The brain is working all the time, too, even while we are sleeping, so it is particularly sensitive to mitochondrial function. Cancer also hijacks mitochondrial machinery to drive its spread. Therefore, the identification of KLF4 as a major regulator of mitochondrial health may have implications beyond those we detailed in this article.”

The findings from this study were published recently in the Journal of Clinical Investigation through an article entitled “Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis.”

KLFs are a family of zinc finger DNA-binding proteins that act as transcription factors to regulate gene expression in a number of tissues throughout the body. In the current study, the investigators found that KLF4 was involved in mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Moreover, the researchers found that cardiac specific KLF4 deficiency had a powerful effect on heart failure in adult mice.

“Xudong made the observation several years ago that mice lacking KLF4 in the heart developed profound heart failure in response to stress,” said senior author Mukesh Jain, M.D., director of the Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine. “In this most recent research, he looked into the mechanisms for why the heart had failed so quickly and made the exciting observation that KLF4 controls major aspects of the mitochondrial biology.”

The researchers compared the effects of cardiac stress on normal mice to those where the cardiac specific KLF4 gene had been knocked out. While the normal mice were able to adapt to the stress, almost 50% of the KLF4-deficient mice succumbed to heart failure within a week and the remaining experienced severe decline in cardiac output. When the Case Western scientists examined the deficient mice at the cellular level they observed massive mitochondrial damage and energy reduction.

“Mitochondria have their own life cycle, and KLF4 controls it,” Dr. Jain noted. “Increasingly, there is a view that mitochondrial dysfunction is a major contributor to many forms of heart failure. The heart has an unrelenting need for energy and thus any mitochondrial dysfunction will impair the heart’s ability to pump blood. If we could target compounds to enhance KLF4 in specific tissues, we may be able to ameliorate disease.”

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