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Review
. 2024 Apr 22;20(7):2532-2554.
doi: 10.7150/ijbs.95122. eCollection 2024.

Autophagy in Its (Proper) Context: Molecular Basis, Biological Relevance, Pharmacological Modulation, and Lifestyle Medicine

Miguel A Ortega  1   2 , Oscar Fraile-Martinez  1   2 , Diego de Leon-Oliva  1   2 , Diego Liviu Boaru  1   2 , Laura Lopez-Gonzalez  2   3 , Cielo García-Montero  1   2 , Miguel Angel Alvarez-Mon  1   2 , Luis G Guijarro  2   4 , Diego Torres-Carranza  1   2 , Miguel A Saez  1   2   5 , Raul Diaz-Pedrero  2   3   6 , Agustin Albillos  1   2 , Melchor Alvarez-Mon  1   2   7
Affiliations
Review

Autophagy in Its (Proper) Context: Molecular Basis, Biological Relevance, Pharmacological Modulation, and Lifestyle Medicine

Miguel A Ortega et al. Int J Biol Sci. .

Abstract

Autophagy plays a critical role in maintaining cellular homeostasis and responding to various stress conditions by the degradation of intracellular components. In this narrative review, we provide a comprehensive overview of autophagy's cellular and molecular basis, biological significance, pharmacological modulation, and its relevance in lifestyle medicine. We delve into the intricate molecular mechanisms that govern autophagy, including macroautophagy, microautophagy and chaperone-mediated autophagy. Moreover, we highlight the biological significance of autophagy in aging, immunity, metabolism, apoptosis, tissue differentiation and systemic diseases, such as neurodegenerative or cardiovascular diseases and cancer. We also discuss the latest advancements in pharmacological modulation of autophagy and their potential implications in clinical settings. Finally, we explore the intimate connection between lifestyle factors and autophagy, emphasizing how nutrition, exercise, sleep patterns and environmental factors can significantly impact the autophagic process. The integration of lifestyle medicine into autophagy research opens new avenues for promoting health and longevity through personalized interventions.

Keywords: ATG proteins; aging; autophagosome; lifestyle habits; pharmacological modulation.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Cellular and molecular basis of autophagy. a) Macroautophagy. The initiation of autophagy and the nucleation of phagophore starts inside the endoplasmic reticulum (ER). During elongation, the phagophore engulfs the cytoplasmic materials. The phagophore closes forming the double-membrane vesicle autophagosome. Then, it fuses with the lysosome (autolysosome), where the inner autophagosomal membrane and cargo are degraded by the lysosomal hydrolases. The remaining catabolites are transported to cytoplasm and recycled by the cell. b) Microautophagy. The cytoplasmic material is captured through direct invagination of the lysosome. c) Chaperone-mediated autophagy (CMA). In multicellular organisms, proteins with the pentapeptide motif KFERQ are recognised and transported by the chaperone HSC70 and cochaperones to the lysosome. The LAMP2A receptor imports the content to the lysosome.
Figure 2
Figure 2
Schematic representation of the key molecular players of macroautophagy, steps and role. mTORC1: mammalian target of rapamycin complex 1, AMP-activated protein kinase: AMPK, ULK1/2: unc-51 like autophagy activating kinase 1/2, FIP200: focal adhesion kinase (FAK)-interacting protein of 200 kDa, PAS: phagophore assembly site, ER: endoplasmic reticulum, GABARAP: gamma-aminobutyric acid receptor-associated protein, VAMPA/B: VAMP-associated protein A/B, PI3KC3-C1: class III phosphatidylinositol 3-kinase complex I, PI3P: phosphatidylinositol 3-phosphate, DFCP1: double FYVE containing protein 1, WIPI1-4: WD-repeat protein interacting with phosphoinositides 1-4, LC3: microtubule-associated protein 1 light chain 3, PE: phosphatidylethanolamine, COPII: coat protein complex II, ESCRT: endosomal sorting complexes required for transport, SNAREs: soluble N-ethylmaleimide sensitive factor attachment protein receptors, HOPS: homotypic fusion and protein sorting, STX17: syntaxin 17, VAMP8: vesicle-associated membrane protein 8, SNAP29: synaptosomal-associated protein 29, FYCO1: FYVE and coiled-coil domain-containing protein 1, RILP: Rab-interacting lysosomal protein, UVRAG: UV-irradiation resistance-associated gene.
Figure 3
Figure 3
A summarized view of the biological relevance of autophagy in balanced and disrupted autophagy.
See this image and copyright information in PMC

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