Autophagy in heart disease pathway

This poster explores the contribution of autophagy to the development of heart disease.

Autophagy is an evolutionarily conserved and fundamental cellular process that entails the breakdown and recycling of defective components within the cell and is crucial for maintaining cellular equilibrium.

The principal process of autophagy comprises a multistep mechanism strongly controlled by proteins of the autophagy-related family called ATGs. Firstly, the membrane structure of the endoplasmic reticulum and mitochondria in the cytoplasm will form autophagic precursors with double membrane cup-shaped separators. Subsequently, autophagic vesicles emerge, and the continuous extension of the septum and the gradual enclosing of debris in the cytoplasm form a closed autophagic vesicle. Next, the autophagosome merges with a lysosome, creating an autolysosome. Finally, the encapsulated substances are disintegrated through the acid hydrolase in the lysosome, and the degraded products are recycled1.

Autophagy in heart disease poster

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Three major autophagy types are identified in mammalian cells: microautophagy, chaperone-mediated autophagy, and macroautophagy2. In microautophagy, cytoplasmic content directly enters the lysosomal membrane through invaginations. By chaperone-mediated autophagy, lysosomes selectively degrade cytosolic proteins harboring the amino acid motif KFERQ to facilitate protein transport into the lysosome. Conversely, macroautophagy is the most frequent and significantly characterized form of autophagy and involves a series of specific steps guided by multiple ATGs.

In the heart, autophagy is essential for the turnover of organelles at low basal levels under normal conditions. It is upregulated in response to stresses such as ischemia/reperfusion and cardiovascular diseases such as heart failure. Heart failure has emerged as the leading cardiovascular disorder in the Western world, a concerning trend that continues regardless of significant progress in medical and surgical treatments.

Furthermore, many other forms of stress can trigger changes in autophagic flux concerning cardiomyocytes, including several indications relevant to heart disease. Pressure stress, such as hypertension or aortic stenosis, initiates substantial increases in cardiomyocyte autophagy, achieving a new, steady-state flux level after the cell has responded with hypertrophic growth3.

Another key protein capable of identifying energy levels in autophagy regulation is AMPK. Via the upstream kinase STK11/LKB1, AMPK can detect cellular ATP/AMP ratio decreases, triggering its activation and autophagy induction. During glucose deprivation, AMPK phosphorylates and activates the tuberous sclerosis complex, TSC1/2, which in turn inactivates the GTPase activating protein RHEB, leading to MTORC1 inhibition and the release of the ULK kinase complex.

This autophagy in heart disease pathway illustrates the overall complex catabolic route that cytoplasmic components are sequestered, degraded, and recycled to survive various stress conditions, including cardiovascular diseases.

References

1. Jiang, B. et al. The role of autophagy in cardiovascular disease: Cross-interference of signaling pathways and underlying therapeutic targets.  Front. Cardiovasc. Med.   10, 1088575 (2023).

2. Gatica, D., Chiong, M., Lavandero, S. & Klionsky, D. J. Molecular Mechanisms of Autophagy in the Cardiovascular System.  Circ. Res.   116, 456–467 (2015).

3. Nishida, K., Kyoi, S., Yamaguchi, O., Sadoshima, J. & Otsu, K. The role of autophagy in the heart.  Cell Death Differ.   16, 31–38 (2009).