We further deliver a molecular rationale for the observed lung phenotype in Trpml3−/− mice, we introduce TRPML3 as a regulator of MMP-12 levels in BALF, we provide a possible mechanism for cell entry of MMP-12, and we propose TRPML3 as a potential drug target for COPD and emphysema treatment. Here, MCOLN3 is linked to pulmonary emphysema.