Department of Biophysics, National University of Uzbekistan, Tashkent, Uzbekistan.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
FEBS J. 2022 Feb;289(3):699-711. doi: 10.1111/febs.16198. Epub 2021 Sep 24.
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.
帕金森病（PD）是一种由中脑多巴胺能神经元丧失引起的进行性神经退行性疾病。神经退行性变的机制与错误折叠蛋白的聚集、氧化应激和线粒体功能障碍有关。考虑到这一点，自噬过程中对不需要的细胞器或蛋白质的清除在神经元中至关重要，并且这些过程的激活在 PD 中可能具有保护作用。细胞溶质的短时间酸化可以激活线粒体自噬和自噬。在这里，我们使用丙酮酸钠和乳酸钠来诱导具有 PD 突变（Pink1、Pink1/Park2、α-突触核蛋白三倍体、A53T）的人成纤维细胞内细胞内 pH 值发生变化。我们发现，乳酸盐和丙酮酸盐在毫摩尔浓度下均可诱导这些细胞的细胞溶质短时间酸化。这在对照和 PD 成纤维细胞中诱导了线粒体自噬和自噬的激活，并防止了细胞死亡。重要的是，向 WT 和 Pink1 KO 小鼠的急性脑片中应用乳酸盐也会导致神经元和星形胶质细胞中 pH 值降低，从而增加线粒体自噬水平。因此，在细胞代谢中起重要作用的化合物使细胞溶质酸化也可以激活线粒体自噬和自噬并保护 PD 家族形式的细胞。
