Scientists discovered a key molecular switch to keep neurons healthy by controlling the disassembly and assembly of their energy-generating powerhouses, the mitochondria. The study illustrates how a protein complex, PP2A-B55\u03b1, acts as a clean-up crew and a controller\u2014choosing to recycle defective mitochondria or build new ones. <\/p>\n
This new knowledge can develop therapies for neurodegenerative disease like Parkinson’s, where dysfunctional mitochondrial maintenance results in the death of neurons.<\/p>\n
Mitochondrial Balance: Cellular Health’s Secret<\/p>\n
Mitochondria are the cell’s power plants that generate the energy the cell needs to survive. But, like all machinery, they deteriorate over time. To stay healthy, cells must discard aging, defective mitochondria by a process known as mitophagy and replace them with shiny new ones via mitochondrial biogenesis. <\/p>\n
Workflow of chromatography techniques coupled with liquid chromatography mass spectrometry (lC- MS) proteomics to identify the protein phosphatase targeting P- UlK1 S556. (CREDIT: Science Advances) <\/p>\n
When this fails\u2014either because of excessive damage or excessive faulty mitochondria\u2014cells begin to fail. This dysfunction is at the root of disease states ranging from Parkinson’s disease to super-orphan mitochondrial diseases affecting muscle, eyes, and brain.<\/p>\n
Until now, researchers knew that proteins like Parkin and PINK1 are responsible for tagging faulty mitochondria for degradation. They did not know, however, how the cell is capable of sensing when to activate repairing. New research conducted by Valentina Cianfanelli at Roma Tre University<\/a> and Francesco Cecconi of Universit\u00e0 Cattolica del Sacro Cuore<\/a> in Rome names PP2A-B55\u03b1 as the link between these two mutual occurrences.<\/p>\n The Discovery: PP2A-B55\u03b1 the Mitochondrial Regulator<\/p>\n Using human cell cultures and fruit fly models, researchers found that PP2A-B55\u03b1 is an enzyme that regulates mitochondrial turnover even under non-stressed, normal conditions. In human neuron-like cells, it is responsible for “basal mitophagy,” the normal recycling that keeps energy in equilibrium. That is, PP2A-B55\u03b1 is not active only in cellular stress\u2014it works behind the scenes to regulate ratios of mitochondria to a neuron’s energy needs.<\/p>\n Cianfanelli\u2019s team also discovered that the enzyme interacts with the Parkin-PARIS-PGC-1\u03b1 pathway, which controls the production of new mitochondria. Normally, a protein called PARIS blocks mitochondrial creation by suppressing PGC-1\u03b1, the main driver of biogenesis. When cells need more mitochondria, Parkin tags PARIS for destruction, allowing PGC-1\u03b1 to restart production. PP2A-B55\u03b1 plays a key role in this process by modifying PARIS through phosphorylation, effectively determining whether it\u2019s ready for Parkin to remove it.<\/p>\n PP2A- B55\u03b1 rescues neurodegenerative phenotypes in flies in a Parkin- dependent manner. (CREDIT: Science Advances) <\/p>\n When PP2A-B55\u03b1 was low in the gene-mutated fruit flies in the PINK1 gene\u2014a potent inducer of Parkin\u2014their mitochondrial abnormalities and motor impairments were corrected. The flies ascended more quickly, and their mitochondria once more had a typical appearance. But this repair did not occur when Parkin was lacking, therefore confirming that PP2A-B55\u03b1 acts through the Parkin-dependent pathway.<\/p>\n A Delicate Coordination Between Destruction and Renewal<\/p>\n Decreasing the levels of B55\u03b1 was seen to make the mitochondria<\/a> healthier by causing new development of new mitochondria, and not by increasing mitophagy. Unusually, decreasing a second protein, PARIS, had similar results\u2014increasing the development of mitochondria without affecting recycling. This suggests that PP2A-B55\u03b1 is a molecular switch that allows neurons to have exactly the right number of mitochondria.<\/p>\n B55, he said on the other hand, promotes the elimination of defective mitochondria through mitophagy. It suppresses excessive generation of new organelles on the other, maintaining the assembly-disassembly process under control. The dual-tier regulation prevents neurons from wasting energy producing unnecessary mitochondria or putting themselves at risk by not producing enough of them.<\/p>\n Implications for Parkinson’s and Beyond<\/p>\n In Parkinson’s disease, mitochondrial loss is a mechanism of death in dopamine-producing neurons that contribute to the disease’s movement deficit. The study’s findings suggest that it is possible to restore mitochondrial equilibrium and rescue these neurons by inhibiting PP2A-B55\u03b1. <\/p>\n Parkin- induced hela cells depleted for B55\u03b1 were stained for mtdnA and hoechst 33342. (B) Quantification of mtdnA\/cell area ratio for cells as seen in (A). (CREDIT: Science Advances) <\/p>\n In animal models of Parkinson’s disease, inhibiting B55\u03b1 activity enhanced motor impairment and reversed mitochondrial dysfunction, providing the potential for therapies that could prevent or even reverse neurodegeneration.<\/p>\n Apart from Parkinson’s<\/a>, the discovery could have implications for a wide range of mitochondrial disease. Because failure of mitochondria also underlies muscle disease and even cancer, control of B55\u03b1 activity can stabilize energy production in huge numbers of tissue. <\/p>\n Cecconi described his lab as trying to identify small molecules that will selectively cause change in B55\u03b1 activity in the brain and thus come up with a “universal” drug that will correct mitochondrial balance across diverse diseases.<\/p>\n The Bigger Picture<\/p>\n The study used an experimental design on a large scale involving animal and human models to confirm PP2A-B55\u03b1’s function. Cells of human-like neurons were cultured and induced to decrease the amounts of B55\u03b1, and fruit fly models helped to show the behavioral effects of such change in molecules. <\/p>\n All significant Cellular Compartments in which the 2276 genes (of 4417) are negatively regulated are mainly enriched. (CREDIT: Science Advances) <\/p>\n With advanced biochemical techniques, researchers tracked how protein levels and interaction responded when B55\u03b1 was removed. This exact mapping revealed a delicate yet coordinated network that allows the unobstructed functioning of mitochondria.<\/p>\n Interestingly, researchers also speculate that the molecular toggle has a contribution towards exercise-induced mitophagy\u2014a physiological process in which exercise revives mitochondria. Since exercise has been found to activate mitochondrial function, PP2A-B55\u03b1 can be included in the feedback mechanism that maintains energy production homeostasis<\/a> with exercise and stress adaptation.<\/p>\n Practical Implications of the Research<\/p>\n This research can be the basis for new therapies that protect neurons and improve mitochondrial function in aging and disease. By controlling PP2A-B55\u03b1, scientists will someday fix mitochondrial dysregulation in Parkinson’s, muscular dystrophies, and other illnesses based on cellular energy collapse.<\/p>\n The discovery also offers hints on how your everyday activities, including exercise, might influence molecular processes that keep your muscle and brain healthy.<\/p>\n