A team of researchers from the Università Cattolica in Rome, in collaboration with Roma Tre University, has identified a regulatory protein called PP2A-B55α (also known as PPP2R2A), that functions as a critical molecular switch in mitochondrial homeostasis, balancing the removal of damaged mitochondria and the formation of new ones. These findings, published in Sciences Advances, showed that modulating the activity of PP2A-B55α in a model of Parkinson’s disease reduced the disease’s motor symptoms and noted it could also be a therapeutic target for other mitochondrial diseases.
PP2A-B55α is a regulatory subunit of the protein phosphatase 2A (PP2A) complex, which removes phosphate groups from other proteins. Unlike protein kinases, which are well-characterized for their role in mitochondrial regulation, the role of phosphatases is less understood.
The new research showed that PP2A-B55α controls mitochondrial turnover through mitophagy, which is the selective degradation of damaged mitochondria, and also inhibits mitochondrial biogenesis in steady-state conditions. The researchers found that PP2A-B55α influences both early and late events in the mitophagy process.
Noting its role in Parkinson’s disease, the researchers wrote: “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.”
The study describes how at the early stages of mitochondrial damage, PP2A-B55α activates ULK1, a kinase involved in autophagy, by dephosphorylating it. This enables the “eat me” signal on damaged mitochondria. Hours later, it also promotes the nuclear translocation of TFEB, which drives the transcription of autophagy and lysosome-related genes, supporting sustained mitophagy.
“Parkin-mediated mitophagy depends on both early regulatory events, occurring minutes after mitochondrial damage… and later events occurring several hours after induction… We found that both early and late phases of mitophagy are affected by PP2A-B55α,” the researchers wrote.
PP2A-B55α also affects mitochondrial biogenesis via its regulation of the Parkin-PARIS-PGC-1α axis. It stabilizes PARIS, a transcriptional repressor that inhibits PGC-1α, a key activator of mitochondrial gene expression. By depleting PP2A-B55α, the repression is lifted, enhancing mitochondrial production.
To find out what effect repressing PP2A-B55α might have, the team turned to fruit fly models of Parkinson’s disease. “We observed that by reducing B55 levels we can improve both the motor defects and the mitochondrial alterations typical of the disease,” noted senior author Francesco Cecconi, PhD, a professor of biochemistry at Università Cattolica and lead author Valentina Cianfanelli, PhD, an associate professor at Rome Tre University. “This effect requires the presence of the Parkin factor and acts primarily on mitochondrial biogenesis.”
Earlier studies had implicated the E3 ubiquitin ligase Parkin in regulating mitophagy, but the connection between mitophagy and mitochondrial biogenesis was unclear. The current research addresses this gap by identifying PP2A-B55α as a dual-function regulator that coordinates both processes through Parkin.
The findings have potential clinical implications not only for Parkinson’s disease, where loss of mitochondrial integrity contributes to dopaminergic neuron death, but also for mitochondrial myopathies and possibly cancers. “Controlling B55 could become a promising approach in oncology,” said Cecconi, noting the role that mitochondrial dynamics play in tumor cell plasticity and treatment resistance.
Additionally, “these findings indicate that PP2A-B55α–mediated regulation of mitochondrial homeostasis may also be relevant to some additional human neurodegenerative disorders characterized by unbalanced mitophagy and mitochondrial biogenesis, such as mitochondrial myopathies and Duchenne’s muscular dystrophy,” the researchers wrote.
The next steps for the team involve screening for small molecules that can safely and selectively modulate PP2A-B55α in neuronal cells. This work could lay the foundation for targeted therapies addressing a range of mitochondrial disorders, especially those currently lacking effective treatments.
