Activation of autophagy is also part of the cellular response to stressors that inflict protein or organelle damage (i.e. oxidative stress, ER stress, genetic mutations) and to challenges that require major adaptive changes in proteome and organelle content to assure cellular survival (i.e. nutrient and growth factor withdrawal, infection or hypoxia) [4]. During nutrient deprivation, autophagy breaks down proteins to replenish the pool of free amino acids and increase cellular ATP levels [5]. The discovery of lipophagy (macroautophagy degradation of lipid droplet triglycerides into free fatty acids [6••]) and glycophagy (macroautophagy and microautophagy degradation of glycogen stores into oligosaccharides

and glucose [7]) have reinforced the contribution of autophagy to metabolic homeostasis. Lipophagy also exerts a protective Pembrolizumab price function against lipotoxicity, and in fact, upregulation of the transcription factor EB (TFEB), which controls lysosomal biogenesis and activates macroautophagy, prevents diet-induced obesity and the metabolic syndrome [8•• and 9••]. CMA can Selleck ERK inhibitor also modulate cellular energetics through the regulated degradation of enzymes involved in distinct metabolic pathways [10 and 11•]. Alterations

in autophagy occur in systemic diseases such as cancer [12], metabolic dysfunction [6••] and vascular instability [13] and in organ-specific pathologies such as neurodegeneration [14], cardiomyopathies and myopathies [15 and 16], non-alcoholic fatty liver disease Anacetrapib [17] or Crohn’s disease [18••]. Next, we summarize some emerging themes in the relationship of autophagy and disease. The multi-step nature of autophagy makes it vulnerable to failure at different levels (Figure 1). Identifying the step(s) affected in disease is important because of the distinct downstream consequences and therapeutic implications. Pathologies affecting each of the steps in macroautophagy have been described (Figure 2). Reduced ability to recognize cargo

can originate from alterations in the degradation tags or in the adaptor molecules that bridge these tags with the autophagic machinery. For example, defective mitochondria turnover by mitophagy in familial Parkinson’s disease (PD) has been linked to recessive mutations in parkin and PINK1, proteins responsible for mitochondrial priming for mitophagy [19]. Mutations in the adaptor p62 have been associated with Paget disease and amyotrophic lateral sclerosis (ALS) [20]. Abnormal interactions of pathogenic proteins with autophagy adaptors can also limit cargo recognition. For example, aberrant binding of pathogenic huntingtin to p62 prevents selective recognition of mitochondria, lipid droplets, and even cytosolic aggregates of the mutant protein in neurons from Huntington’s disease (HD) patients [21•]. Failure to selectively recognize and degrade energy stores also compromises the energetic balance of the affected neurons.