Metabolically induced intracellular pH changes activate mitophagy, autophagy, and cell protection in familial forms of Parkinson's disease
| Autor: | Noemí Esteras, Olga Stelmashchuk, Alexander V. Gourine, Ulugbek Zakirovich Mirkhodjaev, A. V. Berezhnov, Andrey Y. Abramov, Plamena R. Angelova, Henry Houlden, Nafisa R. Komilova |
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| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Ubiquitin-Protein Ligases Intracellular pH PINK1 Biochemistry Sodium Lactate Mice chemistry.chemical_compound Sodium pyruvate Pyruvic Acid Mitophagy Autophagy medicine Animals Humans Molecular Biology Mice Knockout Chemistry Dopaminergic Neurons Neurodegeneration Parkinson Disease Cell Biology Fibroblasts Hydrogen-Ion Concentration medicine.disease Mitochondria Cell biology Oxidative Stress Cytosol Cytoprotection Astrocytes alpha-Synuclein Protein Kinases |
| Zdroj: | The FEBS Journal. 289:699-711 |
| ISSN: | 1742-4658 1742-464X |
| Popis: | Parkinson's disease (PD) is a progressive neurodegenerative disorder induced by the loss of dopaminergic neurons in midbrain. The mechanism of neurodegeneration is associated with aggregation of misfolded proteins, oxidative stress, and mitochondrial dysfunction. Considering this, the process of removal of unwanted organelles or proteins by autophagy is vitally important in neurons, and activation of these processes could be protective in PD. Short-time acidification of the cytosol can activate mitophagy and autophagy. Here, we used sodium pyruvate and sodium lactate to induce changes in intracellular pH in human fibroblasts with PD mutations (Pink1, Pink1/Park2, α-synuclein triplication, A53T). We have found that both lactate and pyruvate in millimolar concentrations can induce a short-time acidification of the cytosol in these cells. This induced activation of mitophagy and autophagy in control and PD fibroblasts and protected against cell death. Importantly, application of lactate to acute brain slices of WT and Pink1 KO mice also induced a reduction of pH in neurons and astrocytes that increased the level of mitophagy. Thus, acidification of the cytosol by compounds, which play an important role in cell metabolism, can also activate mitophagy and autophagy and protect cells in the familial form of PD. |
| Databáze: | OpenAIRE |
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