Metabolically induced intracellular pH changes activate mitophagy, autophagy, and cell protection in familial forms of Parkinson's disease

• Published in: The FEBS journal 2022-02, Vol.289 (3), p.699-711
• Main Authors: Komilova, Nafisa R., Angelova, Plamena R., Berezhnov, Alexey V., Stelmashchuk, Olga A., Mirkhodjaev, Ulugbek Z., Houlden, Henry, Gourine, Alexander V., Esteras, Noemi, Abramov, Andrey Y.
• Format: Article
• Language: English
• Subjects: Acidification; alpha-Synuclein - genetics; Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Autophagy; Autophagy - drug effects; Autophagy - genetics; Brain slice preparation; Cell activation; Cell death; Cytoprotection - drug effects; Cytosol; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Fibroblasts; Fibroblasts - drug effects; Humans; Hydrogen-Ion Concentration - drug effects; Intracellular; lactate; Lactic acid; Mesencephalon; Metabolism; Mice; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Mitophagy; Mitophagy - drug effects; Mitophagy - genetics; Movement disorders; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurons; Organelles; Oxidative stress; Oxidative Stress - drug effects; Parkinson Disease - diagnostic imaging; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; pH effects; Phagocytosis; Protein folding; Protein Kinases - genetics; Proteins; PTEN-induced putative kinase; pyruvate; Pyruvic acid; Pyruvic Acid - pharmacology; Sodium; Sodium lactate; Sodium Lactate - pharmacology; Synuclein; Ubiquitin-Protein Ligases - genetics
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16198

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. Metabolites pyruvate and lactate induce a short‐term acidification of the cytosol. This leads to activation of mitophagy/autophagy and cell protection in fibroblasts from patients with familial forms of Parkinson's disease as well as in rat neurons and astrocytes with Parkinson's disease‐associated PINK1 deficiency.