Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified “H⁺ leak” pathway. Here we show that TMEM175, a genetic risk factor for Parkinson’s disease (PD), mediates the lysosomal H⁺ leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel’s H⁺ conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.

溶酶体需要 pH 4.5 至 5.0 之间的酸性腔才能有效消化大分子。这种最佳 pH 值是通过 V-ATP 酶产生的质子流入和通过未识别的“H ⁺泄漏”途径流出来维持的。在这里，我们表明TMEM175（帕金森病 (PD) 的遗传风险因素）介导溶酶体 H ⁺通过充当溶酶体膜（LyPAP）上的质子激活、质子选择性通道来泄漏。超出正常范围的酸化会有效激活 LyPAP，从而终止溶酶体的进一步酸化。内源性多不饱和脂肪酸和合成激动剂也激活 TMEM175 以触发溶酶体质子释放。TMEM175 缺乏会导致溶酶体过度酸化，蛋白水解活性受损，并促进 α-突触核蛋白在体内聚集。突变和 pH 标准化分析表明通道的 H ⁺电导对于正常的溶酶体功能至关重要。因此，通过细胞信号调节 LyPAP 可以动态调节内体和溶酶体的最适 pH 值，以调节溶酶体降解和 PD 病理学。