![]() Phosphorylation of ATG14, BECN1, and/or AMBRA1 by ULK1 promotes PIK3C3/VPS34 activation and, in some cases, recruitment to the endoplasmic reticulum (ER) ( Di Bartolomeo et al., 2010 Russell et al., 2013 Park et al., 2016a Park et al., 2018). ULK1 phosphorylates several components of the PIK3C3/VPS34 kinase complex that contains, in addition to PIK3C3/VPS34, PIK3R4/VPS15, BECN1, NRBF2 and other regulatory proteins such as ATG14, AMBRA1, SH3GLB1, RUBCN or UVRAG ( Kihara et al., 2001 Itakura et al., 2008 Youle and van der Bliek, 2012). ![]() ![]() The ULK complex is comprised of ULK1 (Atg1 in yeast) or ULK2, and several interacting proteins: ATG13, RB1CC1 and ATG101. Macroautophagy (hereafter referred to as autophagy) begins with the initiation of the double-membrane phagophore by the ULK complex. This review will describe the various autophagic mechanisms that cells employ to combat metabolic perturbations and will touch on how these responses are important for systemic metabolism in health and disease. These studies highlight a central role for autophagy in metabolic maintenance. Upregulated autophagy increases median lifespan by 12% and decreases susceptibility to age-related diseases such as cancer ( Fernandez et al., 2018). A recent study in mice revealed the potential benefits of basal autophagy upregulation. Autophagy may also regulate circadian metabolic cycles by degrading core circadian proteins such as CRY1 ( Toledo et al., 2018). Autophagy in mouse hypothalamic neurons regulates food intake and organismal energetics ( Kaushik et al., 2011). Even when grown with sufficient food, these autophagy-deficient adults die in less than three months due to increased susceptibility to infection and neurodegeneration ( Karsli-Uzunbas et al., 2014). Autophagy-deficient mouse embryos die within a day of birth ( Kuma et al., 2004), and adult mice induced to be autophagy-deficient die within 24 h of starvation due to hypoglycemia. Among other roles, selective autophagy allows the cell to adapt to lipid imbalance, glucose scarcity, amino acid deprivation, and iron shortage, and also facilitates cellular remodeling to accommodate major shifts in metabolism ( Gatica et al., 2018).ĭue to its diverse roles in maintaining metabolic homeostasis, autophagy plays a major role in general metabolic health and organismal development autophagic imbalance has been linked to several mammalian pathologies including diabetes ( Marasco and Linnemann, 2018), neurodegeneration ( Frake et al., 2015) and cancer ( Galluzzi et al., 2015). Discriminant selection of autophagic cargo allows for the removal of dysfunctional/superfluous organelles as well as the generation of specific nutrients in response to environmental changes, thereby promoting cell survival and organismal health. In addition, several forms of selective macroautophagy are now recognized, revealing a dynamic role of autophagy in cellular metabolism ( Mizushima and Komatsu, 2011). During starvation, degradation by non-selective autophagy provides simple macromolecules that can be utilized for essential anabolic synthesis. This process occurs continuously at a low, basal level facilitating the turnover and recycling of cytoplasmic contents but is also upregulated under conditions of nutrient deprivation. ![]() Non-selective autophagy describes the random engulfment and subsequent degradation of cytoplasmic material such as proteins and/or organelles ( Dikic and Elazar, 2018). Autophagy can be either selective or non-selective. We also discuss the role of autophagy in the development and maintenance of adipose tissue, an emerging player in systemic metabolic homeostasis, and describe what is currently known about the complex relationship between autophagy and cancer.Īutophagy is a highly conserved eukaryotic pathway for maintaining cellular homeostasis through the degradation of superfluous and/or damaged intracellular materials. We outline the metabolic signals that activate these pathways, the mechanisms involved, and the downstream effects and implications while recognizing yet unanswered questions. Here we highlight the co-regulation of autophagy and metabolism with a special focus on selective autophagy that, along with bulk autophagy, plays a central role in regulating and rewiring metabolic circuits. These functions of autophagy are intimately connected to the regulation of metabolism, and the metabolic status of the cell in turn controls the nature and extent of autophagic induction. Autophagy functions basally for cellular quality control and is induced to act as an alternative source of basic metabolites during nutrient-deprivation. Autophagy is an evolutionarily conserved lysosome/vacuole-dependent catabolic pathway in eukaryotes.
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