Mitochondria Protein KLF4 Protects Heart Stress-Induced Failure

In a new study entitled “Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis” scientists at the Case Cardiovascular Research Institute report the discovery of a mitochondria protein – Kruppel-like factor 4 (KLF4) – that is crucial for maintaining heart health and protection from aging. The study was published in the Journal of Clinical Investigation (JCI).

Mitochondria are defined as cells’ energy powerhouse, since they are fundamental in producing the energy our cells need to function, as Xudong Liao, PhD, study first author and assistant professor in cardiovascular medicine at Case Western Reserve University School of Medicine explained, “Some cells are incredibly dependent on mitochondria, particularly the heart and brain. 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 mitochondria health may have implications beyond those we detailed in this article.”

Following a previous observation, study lead author Mukesh Jain, MD, director of the Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine noted, “Xudong made the observation several years ago that mice lacking KLF4 in the heart developed profound heart failure in response to stress.” As a result, the team decided to investigate “the mechanisms for why the heart had failed so quickly and made the exciting observation that KLF4 controls major aspects of the mitochondrial biology,” as well as the role of KLF4 in the hearts of adult mice. They generated mice with a cardiac-specific deletion of KL4 and observed that mice developed cardiac dysfunction with aging and succumbed to heart failure within a week, while control mice were capable of adapting to cardiac stress conditions and didn’t die. The researchers also discovered that KLF4-heart depleted mice exhibited severe damage to mitochondria, accompanied by a significant decrease in energy production. The team performed further studies and determined that KLF4 is a critical transcription factor regulating the formation of new mitochondria, and also for the repair and maintenance of those already formed.

These findings have an important clinical relevance since, “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,” as explained by Mukesh Jain, MD. Now the team is now focused on developing a strategy to increase KLF4 levels because, Jain concluded, “If we could target compounds to enhance KLF4 in specific tissues, we may be able to ameliorate disease.”