Researchers at UCLA have made a significant breakthrough in understanding the connection between impaired autophagy and heart failure. Autophagy is the process by which the body removes damaged cell parts, allowing for cellular repair and energy production. However, when this process is impaired, it can lead to various disorders, including heart failure.
The research team, led by Dr. E. Dale Abel and Dr. Quanjiang Zhang, discovered a signaling pathway that connects impaired autophagy to the control of a coenzyme called NAD+. NAD+ is essential for cellular metabolism and plays a crucial role in maintaining overall cellular function. The findings of this study may have implications for the development of new therapies for heart failure.
Heart failure remains one of the leading causes of mortality globally, with a pressing need for new treatments that can improve cardiac function and increase survival rates. Identifying the pathway that links impaired autophagy to increased breakdown of NAD+ could open up innovative avenues for therapeutic intervention.
The researchers describe autophagy as the body’s cellular recycling system. It allows cells to break down damaged or dysfunctional parts and repurpose them into new, usable components for repair or energy production. When autophagy is impaired, dysfunctional mitochondria can build up, leading to inflammation and other responses that can cause cell death or dysfunction.
Previous studies have proposed that the degradation of specific proteins involved in metabolism can also contribute to cardiac dysfunction in the setting of impaired autophagy. However, the present study identified NAD+ depletion as a new mechanism that leads to heart muscle cell dysfunction.
Using a mouse model with autophagy dysfunction in heart cells, the researchers discovered that autophagy regulates an enzyme called NNMT, which increases levels in the heart failure model. By inhibiting the activity of this enzyme using a small molecule, they observed an improvement in heart failure, despite the persistence of autophagy failure.
The study revealed a chain of events that explains how impaired autophagy can lead to cardiac dysfunction. It begins with the accumulation of a protein called SQSTM1, which activates a signaling protein known as NF-κB. NF-κB then enters the nucleus and increases gene activity that encodes the NNMT enzyme. As a result, NAD+ precursors are broken down, ultimately leading to decreased NAD+ levels and mitochondrial and cardiac dysfunction.
Understanding this pathway has shed light on the connection between NAD+ metabolism and autophagy. It highlights the potential for a new therapy that can reverse mitochondrial dysfunction and improve heart failure by preventing NAD+ loss and boosting its levels in cardiac muscle.
Further research is needed to investigate the efficacy of this potential therapy and its implications for the treatment of heart failure. However, these findings provide a significant step forward in understanding the underlying mechanisms of cardiac dysfunction and offer hope for the development
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
