ArticleThe FEBS journal2013
N-terminal phosphorylation of protein phosphatase 2A/Bβ2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival.
Article in The FEBS journal, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 46 citations in OpenAlex.
- Abnormal Amyloidogenesis Identified in Plasma of Patients with Spinocerebellar Ataxia Type 12.Cerebellum (London, England) · 2026Article
- PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis.Autophagy · 2025Article
- Histone deacetylase 7 mediates lipopolysaccharide-inducible mitochondrial fission in macrophages.Journal of cell science · 2025Article
- DRP1, fission and apoptosis.Cell death discovery · 2025Review
- De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.Human molecular genetics · 2025Article
- Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.Cerebellum (London, England) · 2024Article
- Role of Bβ1 overexpression in the pathogenesis of SCA12.Movement disorders : official journal of the Movement Disorder Society · 2024Article
- Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.Research square · 2024Article
- Mitochondrial dynamics in macrophages: divide to conquer or unite to survive?Biochemical Society transactions · 2023Article
- Review
- Protein phosphatase 2A - structure, function and role in neurodevelopmental disorders.Journal of cell science · 2021Review
- Mitochondrial Fusion and Fission in Neuronal Death Induced by Cerebral Ischemia-Reperfusion and Its Clinical Application: A Mini-Review.Medical science monitor : international medical journal of experimental and clinical research · 2020Review
- Deletion of a Neuronal Drp1 Activator Protects against Cerebral Ischemia.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- The cell biology of mitochondrial membrane dynamics.Nature reviews. Molecular cell biology · 2020Review
- The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-α.Frontiers in cellular and infection microbiology · 2020Article
- Mitochondrial Morphofunction in Mammalian Cells.Antioxidants & redox signaling · 2019Review
- Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology.American journal of physiology. Cell physiology · 2019Review
- Adrenergic Regulation of Drp1-Driven Mitochondrial Fission in Cardiac Physio-Pathology.Antioxidants (Basel, Switzerland) · 2018Review
- Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy.The EMBO journal · 2018Article
- Protein phosphatase 2A regulates the p38 signaling pathway to affect the migration of astrocytes.Molecular medicine reports · 2018Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The neuron-specific Bβ2 regulatory subunit of protein phosphatase 2A (PP2A), a product of the spinocerebellar ataxia type 12 disease gene PPP2R2B, recruits heterotrimeric PP2A to the outer mitochondrial membrane (OMM) through its N-terminal mitochondrial targeting sequence. OMM-localized PP2A/Bβ2 induces mitochondrial fragmentation, thereby increasing susceptibility to neuronal insults. Here, we report that PP2A/Bβ2 activates the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) by dephosphorylating Ser656, a highly conserved inhibitory phosphorylation site targeted by the neuroprotective protein kinase A-A kinase anchoring protein 1 complex. We further show that translocation of PP2A/Bβ2 to mitochondria is regulated by phosphorylation of Bβ2 at three N-terminal serines. Phosphomimetic substitution of Ser20, Ser21, and Ser22 renders Bβ2 cytosolic, blocks Drp1 dephosphorylation and mitochondrial fragmentation, and abolishes the ability of Bβ2 overexpression to induce apoptosis in cultured hippocampal neurons. Alanine substitution of Ser20-Ser22 to prevent phosphorylation has the opposite effect, promoting association of Bβ2 with mitochondria, Drp1 dephosphorylation, mitochondrial fission, and neuronal death. OMM translocation of Bβ2 can be attenuated by mutation of residues in close proximity to the catalytic site, but only if Ser20-Ser22 are available for phosphorylation, suggesting that PP2A/Bβ2 autodephosphorylation is necessary for OMM association, probably by uncovering the net positive charge of the mitochondrial targeting sequence. These results reveal another layer of complexity in the regulation of the mitochondrial fission-fusion equilibrium and its physiological and pathophysiological consequences in the nervous system.
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Registered trials
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