Investigating the role of Bax/Bak as a driver of inflammation in aging

Senescent cells drive age-related tissue dysfunction partially via the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. 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 die. Here, we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), depends on the formation of BAX and BAK macropores leading to the release of mitochondrial DNA (mtDNA) into the cytosol, which in turn activates the cGAS-STING pathway, a major regulator of the SASP. Importantly, we found that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal, unexpectedly, that apoptosis and senescence are regulated by similar mitochondrial-dependent mechanisms, and that sub-lethal mitochondrial apoptotic stress is a major driver of the SASP. We also provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a new therapeutic avenue to improve healthspan. Overall design: Aged mice (20 months old) were treated with the Bax inhibitor, BAI1, three times a week for three months. The drug was delivered by IP injections. (April 13, 2024) Update: The old processed files were aggregated matrix using Cellranger aggr by combining two samples together. To make it more clear and easy to access, the processed data were updated with the matrix for each sample separately.