小柯机器人

美国梅奥诊所João F. Passo等研究人员合作发现，凋亡应激引起衰老过程中mtDNA的释放并驱动SASP。相关论文于2023年10月11日在线发表在《自然》杂志上。

研究人员发现发生在线粒体亚群中的线粒体外膜通透性（MOMP）是细胞衰老的一个特征。这个过程被称为少数MOMP （miMOMP），需要BAX和BAK大孔使线粒体DNA（mtDNA）释放到细胞质中。细胞质mtDNA反过来激活cGAS-STING通路，这是慢性衰老相关分泌表型（SASP）的主要调节因子。研究人员发现体内抑制MOMP可减少炎症标志物，改善老年小鼠的健康状况。这些研究结果表明，细胞凋亡和衰老是由类似的线粒体依赖机制调节的，亚致死线粒体凋亡应激是SASP的主要驱动因素。研究人员提供了概念性证明，抑制miMOMP诱导的炎症可能是改善健康的治疗途径。

据了解，衰老细胞通过诱导SASP部分驱动与年龄相关的组织功能障碍。线粒体是SASP的主要调控因子;然而，其潜在的机制尚未阐明。线粒体通常是细胞凋亡所必需的，细胞凋亡是一种不同于细胞衰老的细胞命运。在细胞凋亡过程中，广泛存在的MOMP导致细胞死亡。

附：英文原文

Title: Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author: Victorelli, Stella, Salmonowicz, Hanna, Chapman, James, Martini, Helene, Vizioli, Maria Grazia, Riley, Joel S., Cloix, Catherine, Hall-Younger, Ella, Machado Espindola-Netto, Jair, Jurk, Diana, Lagnado, Anthony B., Sales Gomez, Lilian, Farr, Joshua N., Saul, Dominik, Reed, Rebecca, Kelly, George, Eppard, Madeline, Greaves, Laura C., Dou, Zhixun, Pirius, Nicholas, Szczepanowska, Karolina, Porritt, Rebecca A., Huang, Huijie, Huang, Timothy Y., Mann, Derek A., Masuda, Claudio Akio, Khosla, Sundeep, Dai, Haiming, Kaufmann, Scott H., Zacharioudakis, Emmanouil, Gavathiotis, Evripidis, LeBrasseur, Nathan K., Lei, Xue, Sainz, Alva G., Korolchuk, Viktor I., Adams, Peter D., Shadel, Gerald S., Tait, Stephen W. G., Passos, Joo F.

Issue&Volume: 2023-10-11

Abstract: Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

DOI: 10.1038/s41586-023-06621-4

Source: https://www.nature.com/articles/s41586-023-06621-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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