The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis, 2025, Cianfanelli et al

[Mij]

Abstract​

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 insult, 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.
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[Mij]

Mitochondrial Switch Identified as Drug Target for Parkinson's Disease

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.

 

[Mij]

AI Overview:

"B55 neuronal cells" are human and fruit fly neurons that are a focus of recent research because the B55 protein complex is a crucial regulator of mitochondrial homeostasis. This means it acts as a "molecular switch" that balances the removal of damaged mitochondria (mitophagy) and the creation of new ones (mitochondrial biogenesis) to keep the cell's energy levels in equilibrium. Recent studies highlight its role in both normal, basal conditions and in diseases like Parkinson's, where a dysregulated B55 can impair mitochondrial function.