Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that are primarily responsible for generating adenosine triphosphate (ATP), a chemical energy store molecule used to power the cell. Mitochondrial function declines with age, negatively impacting health, and thus researchers are interested in finding ways to either enhance function to compensate for this decline or find ways to prevent and reverse the loss of mitochondrial activity. Most currently available approaches fail to much improve on the effects of exercise on this front, and appear to largely work by improving quality control mechanisms that have evolved to remove damaged mitochondria. Here, researchers report on a novel target to improve mitochondrial function in older individuals, one that improves both quality control and generation of new mitochondria.
Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number.
Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the damage, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS.
PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.
Link: https://doi.org/10.1126/sciadv.adw7376
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