Autophagy and mitophagy regulatory pathways

Autophagy and mitophagy regulatory pathways are essential cellular degradation processes that maintain homeostasis by recycling damaged organelles and misfolded proteins. Autophagy involves the formation of double-membrane autophagosomes that sequester cytoplasmic components for degradation by lysosomes, while mitophagy is the selective removal of dysfunctional mitochondria (Mizushima & Komatsu, 2011; Youle & Narendra, 2011). These pathways are governed by a complex network of proteins, including the ULK1 complex, the PI3K complex, and the PINK1-Parkin axis for mitochondrial quality control (Pickles et al., 2018). Dysregulation of these processes is a hallmark of various pathologies, particularly neurodegenerative diseases like Parkinson's and Alzheimer's, where the accumulation of toxic aggregates and damaged mitochondria leads to neuronal death (Klionsky et al., 2021). In cancer, autophagy plays a dual role, acting as a tumor suppressor in early stages but promoting survival in established tumors by providing nutrients under metabolic stress. Therapeutic strategies aim to either induce these pathways to clear toxic debris or inhibit them to sensitize cancer cells to treatment, using agents such as mTOR inhibitors or lysosomotropic drugs.

Other names

MacroautophagySelective autophagyMitochondrial autophagyPINK1-Parkin pathwayULK1-mediated autophagyCMA (Chaperone-mediated autophagy)

Drugs modulate these pathways by inhibiting the Mechanistic target of rapamycin kinase (mTOR) to induce autophagy, activating AMP-activated protein kinase (AMPK), or blocking lysosomal acidification and autophagosome-lysosome fusion to inhibit the degradation phase.