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    • Our current knowledge on autophagy broadly differentiates it

    2024-04-10

    Our current knowledge on autophagy broadly differentiates it into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy mainly involves the sequestration of cytoplasmic contents in a double-walled membrane followed by the fusion with the lysosomes. The lysosomal enzymes facilitate the degradation of the sequestered products. Microautophagy is categorized by the direct engulfment of cytoplasmic cargo by the lysosomes. The last type is the only one where proteins are specifically targeted to lysosomes via signal peptides and coordinated by chaperones located on both sides of the targeted membrane. Selective autophagy including mitophagy, ERphagy, lipophagy, xenophagy to clear mitochondria, endoplasmic reticulum, lipid droplets and invading pathogens respectively are degraded by for maintaining cellular homeostasis [4,5]. In the present review, we focus on the implications of different types of autophagy in the maintenance of health and progression of diseases, thereby deciphering the relevance of autophagy in the human system.
    Autophagy: self-eating mechanism Autophagy as a cytoprotective mechanism is triggered by different stimuli including nutrient deprivation, oxidative stress, hypoxia, protein Misoprostol and toxic molecules to mitigate stress. The process of autophagy initiates with the formation of the isolating membrane and phagophore. During stress conditions, the mammalian target of rapamycin (mTOR) is inactivated, which consequently activates Atg1 (Ulk1 and Ulk2 mammalian homolog) kinase activity. The activation of Atg1/ULK1-2, in turn, causes phosphorylation of Atg13 and FIP200 and auto-phosphorylation of ULK proteins. The phosphorylation and the formation of Atg13-ULK-FIP200 complex recruit other Atg proteins, thereby resulting in the initiation of autophagosome formation [[4], [5], [6], [7]]. The formation of the phagophore membrane is regulated by the class-III phosphatidylinositol 3-kinase (PtdIns3K) complex. This complex comprises PtdIns3KVps34, Vps15/p150, Atg14/mAtg14, and Vps30/Beclin1 [4]. The PtdIns3K complex forms phosphatidylinositol-3-phosphate from phosphatidylinositol, and this complex targets the formation of pre-autophagosomal structure (PAS) through binding of several yeast autophagic proteins, such as Atg18, Atg20, Atg21, and Atg24, to phosphatidylinositol-3-phosphate. The PtdIns3K complex along with the Atg proteins then recruits two ubiquitin-like conjugation systems, namely Atg12-Atg5-Atg16 and Atg8-phosphatidylethanolamine (Atg8-PE), to PAS. These are, in turn, involved in the phagophore membrane elongation and expansion. In the first system, Atg7 activates Atg12, which is then transferred to Atg10 and linked to Atg5. The Atg12-Atg5 complex then binds to the Atg 16, followed by the recruitment of this complex to the phagophore membrane [4]. The Atg5-Atg12 conjugation system is not linked to the activation of autophagy; therefore, as the autophagosome is formed, the Atg5-Atg12-Atg16 complex gets dislodged from the membrane making it a poorer marker for autophagy [8]. Another ubiquitin pathway involves the lipidation of LC3 (Atg8). LC3 is synthesized as pro-LC3, which is cleaved by Atg4 at the C-terminus to form LC3-I. The LC3-I moiety is conjugated to PE with the help of Atg7 and Atg3 to form LC3-II. LC3-II is then recruited on both the membranes of autophagosomes and enables the fusion with the lysosomes [9]. The connection of autophagosomes to the microtubule proteins facilitates their transport to the lysosomes. Moreover, Rab GTPase, involved in membrane trafficking are localized to the late endosomes and lysosomes for their motility and fusion [10]. After the fusion of autophagosome with the vacuole, the cytosolic cargo is broken down by the acidic lysosomal hydrolases [6] (Fig. 1).
    Aging: an unhealthy autophagic recipe Aging in all multicellular organisms is characterized by the decreased ability to combat the environmental stresses that lead to the loss of cellular homeostasis and make the organism prone to many old-age associated diseases. It has been observed that global proteolysis decreases with age. Most of the proteins whose degradation is hindered during aging have been found to be the substrates of lysosomal degradation. This observation connects autophagy to the process of aging. With the onset of aging, macroautophagy gradually subsides, consequently leading to the reduced formation of autophagic vacuoles and improper fusion of the vacuoles with the lysosomes. This finally causes a significant impairment in the protein flux with an accumulation of autophagic vacuoles in old tissues [11,12]. Additionally, the diminished fusion of vacuoles with lysosomes is also attributed to the oxidation of lipids and proteins in the membrane of the lysosomes that make them fragile and unable to fuse with the vacuoles. Intriguingly, the inactivation of many autophagic proteins, such as VPS30/ATG6/beclin1, has been shown to diminish the lifespan extension in C. elegans suggesting that autophagy is essential for increasing the lifespan [11].