Home Medizin Studie gibt Aufschluss darüber, wie eine beeinträchtigte Autophagie eine Rolle bei der Entstehung von Herzversagen spielen kann

Studie gibt Aufschluss darüber, wie eine beeinträchtigte Autophagie eine Rolle bei der Entstehung von Herzversagen spielen kann

von NFI Redaktion

A recent study has shed light on how autophagy, the body’s process of removing damaged cell parts when impaired, may play a role in the development of heart failure. The research team led by Dr. E. Dale Abel, Chairman of the UCLA School of Medicine, and Dr. Quanjiang Zhang, Associate Professor of Medicine at UCLA, identified a signaling pathway that connects autophagy with the control of cellular levels of a key coenzyme called NAD+, which is essential for the functioning of our metabolism. Researchers say these findings could have implications for the treatment of heart failure.

„Heart failure remains one of the most common causes of death, and there is a great need for the development of new therapies that can improve cardiac function and increase survival. Identifying a new signaling pathway that links impaired autophagy, a feature of heart failure, with increased NAD+ depletion could open up new avenues for therapeutic interventions.“

– Dr. E. Dale Abel, Chairman of the UCLA School of Medicine

Autophagy is a natural, self-serving mechanism in which the body removes damaged or dysfunctional parts of a cell and recycles their components for cell repair or energy production. Abel describes it as our body’s cellular recycling system, allowing cells to break down bad parts of themselves and salvage some of those parts to convert them into new, usable parts. Given the crucial role of autophagy in cell degradation and repair, impaired autophagy is known to cause several diseases, including cancer, neurodegeneration, and heart failure.

So far, scientists were unsure of the mechanisms underlying mitochondrial and cardiac dysfunction in the presence of impaired autophagy. One proposed mechanism is the accumulation of dysfunctional mitochondria that occurs when autophagy is impaired, as this buildup can trigger inflammatory and other reactions leading to cell death or dysfunction. Another proposed mechanism is the degradation of specific proteins involved in metabolism, which diminish the function of signaling pathways that regulate heart muscle contraction. The present study identified a new mechanism, namely NAD+ depletion, which leads to the dysfunction of cardiac muscle cells in connection with autophagy.

Using a mouse model with autophagy dysfunction in heart cells, the research team found that autophagy regulates the enzyme NNMT, whose levels were elevated in this model of heart failure. Inhibiting the activity of this enzyme with a small molecule led to an improvement in heart failure, even though autophagy failure persisted.

The study elucidated a chain of events that explains how and why impaired autophagy can lead to cardiac dysfunction. The first step in this chain is the accumulation of a protein called SQSTM1. Increased SQSTM1 activates a signaling protein called NF-κB (also known as RELA). NF-κB enters the cell nucleus and causes increased activity of the gene coding for the enzyme known as Nicotinamide-N-Methyltransferase (NNMT). NNMT ultimately leads to the depletion of NAD+ precursors, which ultimately leads to a decrease in NAD+ levels. Low NAD+ levels then cause mitochondrial and cardiac dysfunction.

Deciphering this signaling pathway has linked NAD+ metabolism and autophagy, pointing to a new potential therapy for reversing mitochondrial dysfunction and improving heart failure by preventing the loss of NAD+ and increasing its levels in cardiac muscle.

Members of the research team included employees of the University of Utah, the University of Iowa, the University of Copenhagen, and City of Hope. Supported by grants from the National Institutes of Health, the American Heart Association, the Fraternal Order of Eagles, the Roy J. Carver Trust, and the Alfred E. Mann Family Foundation.

Source:

University of California – Los Angeles Health Sciences

Journal Reference:

Zhang, Q., et al. (2024) Modulation of mitochondrial and heart function by autophagic flux-controlled NAD+ homeostasis. The EMBO Journal. doi.org/10.1038/s44318-023-00009-w.

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