Pathophysiological relevance of selective autophagy. (a, b) Selective types of autophagy operates constitutively at low levels even under nutrient-rich conditions and mediates turnover of selected cytoplasmic materials through the action of autophagy receptors such as p62 and NBR1. These proteins mediate the elimination of ubiquitinated structures, including protein aggregates (a) and defects in these pathways lead to the disruption of tissue homeostasis, resulting in life-threatening diseases. Defective autophagy is usually accompanied by extensive accumulation of p62-containing aggregates, which enhances its function as a scaffold protein in several signaling cascades such as NF-κB signaling, apoptosis, and Nrf2 activation (b). Such abnormalities might be involved in tumorigenesis and Paget’s disease of bone. (c) During erythroid differentiation, Nix/Bnip3L relocalization to mitochondria leads to their depolarization, which triggers mitophagy. Loss of Nix/Bnip3L causes an arrest in the erythroid maturation arrest, leading to severe anaemia. In response to loss of the mitochondrial membrane potential, Parkin translocates onto the damaged mitochondria in a PINK1-dependent manner, and ubiquitinated proteins present on the outer mitochondrial membrane, which induces mitophagy. Parkinson’s disease-related mutations in the Parkin and PINK1 genes provoke a defect in mitophagy, suggesting this selective type of autophagy has a role in preventing the pathogenesis of the Parkinson’s disease. (d) Specific bacteria invading the cytosol get ubiquitinated and are recognized by autophagy receptors such as p62, NDP52, and optineurin (OPTN). This allows the specific sequestration of the microbes into autophagosomes and their delivery into the lysosomes for degradation. (e) The lipid droplets are probably degraded by autophagy selectively. This selective type of autophagy, lipophagy, supplies free-fatty acids utilized to generate energy through the β-oxidation. Impairments in lipophagy are known to cause accumulation of lipid droplets in hepatocytes and reduced production of AgRP in neurons.
