In their recent publication, Georgakopoulos, Wells and Campanella provide a critical appraisal of the currently available pharmacological modulators of mitophagy.
After depicting our current understanding of mitophagy, the authors describe the available chemical modulators of mitophagy and discuss their mechanism of action, advantages and limitations. They particularly highlight the chemicals’ off-targets effects, often associated with the disruptive effects that they exert on mitochondria.
Through this comprehensive review, the authors raise the need for new and specific modulators of mitophagy in order to improve our understanding of this intriguing pathway.
PINK1–parkin-mediated mitophagy. A schematic representation of the PINK1–parkin pathway of mitophagy, activated by protonophores or mitochondrial toxins, causing a collapse of the mitochondrial membrane potential (DYm). Depolarized mitochondria (red) accumulate PINK1 on their surface triggering the recruitment of the ubiquitin ligase parkin (a). Parkin ampli es the mitophagy signal generated by PINK1, ubiquitinating mitochondrial proteins and thereby providing more ubiquitin substrate for PINK1 to phosphorylate (gray shapes). In this model, the mitophagy receptors NDP52 and OPTN promote the recruitment of ULK1, which drives autophagosome initiation on the surface of mitochondria being disposed (brown). NDP52 and OPTN, following accumulation of PINK1, can drive the process independently from the recruitment of parkin (b). ULK1, unc-51-like autophagy activating kinase 1; NDP52, nuclear dot protein 52; OPTN, optineurin; mito, mitochondrial.
For more information: https://www.nature.com/nchembio/journal/v13/n2/full/nchembio.2287.html