Investigators Discover Mechanisms Connecting Impaired Autophagy, Heart Failure

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A signaling pathway linking autophagy to nicotinamide adenine dinucleotide (NAD+), found indications that NAD+ depletion can lead to heart muscle cell dysfunction.

Investigators identified the mechanism connecting impaired autophagy with heart failure (HF), according to results of a study published in The EMBO Journal.1,2 Autophagy is the body’s process of removing damaged cells, and when impaired, it can cause a variety of disorders, including cancer, neurodegeneration, and HF, according to a press release.1

Heart Failure Diagnosis. Medical Concept | Image Credit: tashatuvango - stock.adobe.com

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“[HF] remains a leading cause of mortality, and there is a strong need to develop new therapies that can improve cardiac function and increase survival. The identification of a new pathway linking impaired autophagy, a characteristic of [HF], and increased NAD+ breakdown could open new avenues for therapeutic intervention,” E. Dale Abel, MD, PhD, chair of the Department of Medicine at the University of California Los Angeles (UCLA), said in the press release.1

3 Key Takeaways

  1. A study conducted by investigators at the University of California Los Angeles (UCLA) has uncovered a signaling pathway connecting impaired autophagy, with heart failure.
  2. The research revealed that depletion of NAD+ resulting from impaired autophagy leads to heart muscle cell dysfunction.
  3. The study suggests a sequence of events involving the accumulation of the protein SQSTM1, which activates nuclear factor kappa-B, leading to increased activity of the gene encoding NNMT.

Although it has been known that an impaired autophagy does play a role in HF, the mechanisms were previously unclear. In the study, investigators from UCLA found a signaling pathway linking autophagy to nicotinamide adenine dinucleotide (NAD+), which is a central part of the metabolism. They found that NAD+ depletion can lead to heart muscle cell dysfunction relating to autophagy.1

Investigators of the study aimed to determine the mechanisms that impair autophagy and cause HF. In mouse models, they disrupted the autophagy initiation in cardiomyocytes by inducible or constitutive knockout of the gene ATG3, which mediates autophagy initiation, according to the investigators. After approximately 1 week, investigators found the ATG3 protein in mice was almost undetectable and the mice’s hearts showed decreases of the MAP1LC3A-II protein and accumulation of MAP1LC3A-I and SQSTM1, according to the study authors.2

Previously, proposed mechanisms had included the build-up of dysfunctional mitochondria, which activates inflammatory and other responses leading to cell death or dysfunction. Another theory was the degradation of proteins in the metabolism, reducing the functional pathways regulating heart muscles.1

However, in this study, investigators found the autophagy regulated the enzyme nicotinamide N-methyltransferase (NNMT), which increased in mice models with HF. They also found that when using a small molecule to prevent the activation of NNMT, improvements of HF were evident, even with dysregulated autophagy continuing.1

Investigators suspect a sequence of events that explains how impaired autophagy leads to cardiac dysfunction, starting with the accumulation of protein SQSTM1. When SQSTM1 increases, it activates nuclear factor kappa-B, a signaling protein, which enters the nucleus and increases the activity of a gene that encodes NNMT. Further, NNMT breaks down NAD+ precursors and lowers the NAD+ levels, causing mitochondrial and cardiac dysfunction, according to the press release.1

Investigators believe that these findings could pave the way for potential therapies that reverse mitochondrial dysfunction and improve HF by preventing NAD+ loss and increasing cardiac muscle.1 In the study, the authors also said this pathway may also be linked to nutrient deprivation, autophagy inductions, and the maintenance of cellular NAD+.2 Further, investigators said that impaired autophagy could contribute to tissue dysfunction, including HF. Other reports have linked NNMT inhibitors to a reversal of diet-induced obesity and prevention of muscle senescence, which the study authors said furthers validating NNMT activity.2

References

  • Study reveals new connection between impaired autophagy and heart failure. News release. EurekAlert. January 11, 2023. Accessed January 15, 2024. https://www.eurekalert.org/news-releases/1030954
  • Zhang Q, Li Z, Li Q, Trammell SA, et al. Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function. EMBO J. 2024. doi:10.1038/s44318-023-00009-w
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