Mitochondrial DNA Mislocalization is an Important Driver of the Senescence-Associated Secretory Phenotype
The presence of lingering senescent cells characteristic of aged tissues is harmful due to the pro-inflammatory signaling produced by these cells, the senescence-associated secretory phenotype (SASP). Researchers here show that mitochondrial stress leading to mislocalization of mitochondrial DNA and a consequent inflammatory response is important in the generation of the SASP. Mammalian cells have evolved an innate immune response to the presence of foreign DNA, but mitochondrial DNA is sufficiently bacteria-like that it can trigger this response. Thus the mitochondrial stress and dysfunction that takes place in aged tissues can provoke some fraction of the chronic inflammation of aging. This process appears to be particularly pronounced in senescent cells.
Senescent cells drive age-related tissue dysfunction partially through 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), 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.