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PHLPP1 regulates PINK1-parkin signalling and life span

Adaptability to intracellular or extracellular cues is essential for maintaining cellular homeostasis. Metabolic signals intricately control the morphology and functions of mitochondria by regulating bioenergetics and metabolism. Here, we describe the involvement of PHLPP1, a Ser/Thr phosphatase, in mitochondrial homeostasis. Microscopic analysis showed the enhanced globular structure of mitochondria in PHLPP1-depleted HEK 293T and C2C12 cells, while forced expression of PHLPP1 promoted mitochondrial tubularity. We show that PHLPP1 promoted pro-fusion markers MFN2 and p-DRP1Ser637 levels using over-expression and knockdown strategies. Contrastingly, PHLPP1 induced mitochondrial fragmentation by augmenting pro-fission markers, t-DRP1 and pDrp1Ser616 upon mitochondrial stress. At the molecular level, PHLPP1 interacted with and caused dephosphorylation of calcineurin, a p-DRP1Ser637 phosphatase, under basal conditions. Likewise, PHLPP1 dimerized with PINK1 under basal conditions. However, the interaction of PHLPP1 with both calcineurin and PINK1 was impaired upon CCCP and oligomycin-induced mitochondrial stress. Interestingly, upon mitochondrial membrane depolarization, PHLPP1 promoted PINK1 stabilization and parkin recruitment to mitochondria, and thereby activated the mitophagy machinery providing a molecular explanation for the dual effects of PHLPP1 on mitochondria under different conditions. Consistent with our in-vitro findings, depletion of phlp-2, ortholog of PHLPP1 in C. elegans, led to mitochondrial fission under basal conditions, extended the lifespan of the worms, and enhanced survival of worms subjected to paraquat-induced oxidative stress.

 

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The passage describes the role of PHLPP1, a Ser/Thr phosphatase, in regulating mitochondrial homeostasis in HEK 293T and C2C12 cells. PHLPP1 promotes mitochondrial tubularity by enhancing pro-fusion markers MFN2 and p-DRP1Ser637 levels and induces mitochondrial fragmentation by augmenting pro-fission markers t-DRP1 and p-DRP1Ser616 upon mitochondrial stress. PHLPP1 interacts with calcineurin and PINK1 under basal conditions, but the interaction is impaired upon CCCP and oligomycin-induced mitochondrial stress. Under mitochondrial membrane depolarization, PHLPP1 promotes PINK1 stabilization and parkin recruitment to mitochondria, and thereby activates the mitophagy machinery, explaining the dual effects of PHLPP1 on mitochondria under different conditions. The depletion of phlp-2, the ortholog of PHLPP1 in C. elegans, leads to mitochondrial fission under basal conditions, extends the lifespan of worms, and enhances survival of worms subjected to paraquat-induced oxidative stress.

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