加拿大麦吉尔大学Heidi M. McBride团队取得一项新突破。他们的论文发现了MAPL通过调控gasdermin蛋白介导的线粒体DNA从溶酶体释放来驱动细胞焦亡。该项研究成果发表在2025年10月13日出版的《自然—细胞生物学》上。

结合全基因组功能遗传筛选和细胞生物学方法，该课题组研究人员发现MAPL通过涉及线粒体和溶酶体的炎症途径诱导焦亡。MAPL过表达促进线粒体DNA在线粒体来源的囊泡中运输到溶酶体，溶酶体在一个需要gasdermin孔的过程中被渗透。这触发mtDNA释放到细胞质中，激活细胞死亡所需的DNA传感器cGAS。此外，多种帕金森病相关基因，包括VPS35和LRRK2，也调节MAPL诱导的焦亡。值得注意的是，MAPL、LRRK2或VPS35的缺失抑制了原代巨噬细胞的炎症细胞死亡，将MAPL和线粒体-溶酶体途径置于免疫信号传导和细胞死亡的下一个环节。

研究人员表示，线粒体对细胞死亡的控制在从癌症到神经退行性疾病机制中起着至关重要的作用。线粒体锚定蛋白连接酶（MAPL）是一种线粒体外膜小泛素样修饰连接酶，是细胞存活的关键决定因素，但MAPL如何控制这一过程的命运尚不清楚。

附：英文原文

Title: MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death

Author: Nguyen, Mai, Collier, Jack J., Ignatenko, Olesia, Morin, Genevieve, Goyon, Vanessa, Janer, Alexandre, Tiefensee Ribeiro, Camila, Milnerwood, Austen J., Huang, Sidong, Desjardins, Michel, McBride, Heidi M.

Issue&Volume: 2025-10-13

Abstract: Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson’s disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria–lysosome pathway at the nexus of immune signalling and cell death.

DOI: 10.1038/s41556-025-01774-y

Source: https://www.nature.com/articles/s41556-025-01774-y