Mitophagy is a selective form of autophagy via which the damaged mitochondria are cleared via the autophagy-lysosome pathway. Mitophagy is an essential part of mitochondrial quality control and plays a key role in maintaining mitochondrial homeostasis. Dyfunctional mitophagy is known to be closely implicated in many diseases, including cancer, aging, and neurodegenerative diseases.
At present, the molecular mechanisms of mitophagy have been extenstively studied. Among them, PINK1 (PTEN-induced kinase 1) and Parkin (an E3 ligase) have been found to play a key role in mediating mitophagy following acute mitochondrial damage. Mutation of PINK1 and Parkin have been linked to familiar type of Parkinson’s Disease (PD), as loss of dopaminergic neurons in the substantia nigra is largely caused by dysregulation of PINK1-Parkin-mediated mitophagy.
Recently, Prof Shen Han-Ming’s team from the National University of Singapore and University of Macau published a research paper titled “Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability” in Life Metabolism. In this study, the researchers first conducted a whole-genome CRISPR-Cas9 screening to identify upstream regulators of PINK1-Parkin-mediated mitophagy. Among several hundreds of positive hits, they focused on one important enzyme, glucose-6-phosphate dehydrogenase (G6PD), which is a rate-limiting enzyme in the pentose-phosphate pathway (PPP), an essential process in glycolysis.
First, they validated the screening results by establishing the G6PD knockout cells and found that deletion of G6PD prevents degradation of mitochondrial proteins induced by mitochondrial depolarizing agents oligomycin and antimycin A (O/A), indicating that G6PD is required for mitophagy. Interestingly, PPP per se is not involved in mitophagy, based on the results that knockout of another PPP enzyme 6-phosphogluconolactonase (PGLS) failed to affect mitophagy. However, the catalytic activity of G6PD is required, as treatment with G6PD inhibitors impairs mitophagy induced by O/A.
Second, the authors examined the molecular mechanisms underlying the regulatory role of G6PD in mitophagy and found that deletion of G6PD causes an inhibition of full-length PINK1 stabilization at mitochondria, and consequently ubiquitin (Ub) phosphorylation.
Third, the authors provided evidence that there is direct interaction between G6PD and PINK1 at mitochondria. Although the majority of G6PD exists in the cytosol, a portion of G6PD localizes to the outer membrane of mitochondria and interacts with OMM protein TOM20 and PINK1, and an inhibition of this interaction by removing the C-terminal domain of G6PD abolished the positive role of G6PD in mitophagy.
Finally, the authors found that the positive regulatory role of G6PD in mitophagy is implicated in maintenance of cell viability, as deletion of G6PD led to a significant decrease in cell viability under mitochondrial stress. This can be reversed by treatment of G6PD KO cells with the mitophagy activator Spautin-1. Taken together, this study has identified a novel role of G6PD in regulating PINK1-Parkin mediated mitophagy, as summarized in the figure below. Results from this study thus demonstrate the possibility that modulation of G6PD function may present a new opportunity in regulation of mitophagy, a strategy for development of intervention for neurodegenerative diseases such as PD.
This work was supported by research grants from both National University of Singapore and University of Macau. Prof Shen’s team at University of Macau focuses on autophagy and metabolism in cancer biology. Detailed information could be found at https://fhs.um.edu.mo/hanming-shen/. Those interested in PhD study or postdoc fellow, please approach Prof Shen directly at hmshen@um.edu.mo.
DOI：10.1093/lifemeta/loae040