Inflammation and mitophagy are mitochondrial checkpoints to aging

Abstract

Cellular and organismal aging have been consistently associated with mitochondrial dysfunction and inflammation. Accumulating evidence indicates that aging-related inflammatory responses are mechanistically linked to compromised mitochondrial integrity coupled with mtDNA-driven CGAS activation, a process that is tonically inhibited by mitophagy.

Fig. 1. Mitophagy-dependent enforcement of the mitochondrial checkpoint in stressed and aging cells.

Mitochondrial dysfunction as spontaneously emerging in aging cells or as elicited by exogenous stressors such as radiation therapy and chemotherapy can be accompanied by the permeabilization of mitochondrial membranes, hence compromising the integrity of the mitochondrial checkpoint. In this context, mitochondrial DNA (mtDNA) released or bulging from permeabilized mitochondria operates as a potent activator of cyclic GMP-AMP synthase (CGAS), hence initiating a stimulator of interferon response cGAMP interactor 1 (STING1)-dependent signaling cascade that culminates with the transactivation of multiple interferon-stimulated genes (ISGs), including interferon beta 1 (IFNB1). The efficient removal of compromised mitochondria as ensured by PTEN induced kinase 1 (PINK1)- and parkin RBR E3 ubiquitin protein ligase (PRKN)-dependent mitophagy tonically suppresses such an aging- and stress-associated inflammatory phenotype. Of note, mitochondrial outer membrane permeabilization (MOMP) as mediated by BCL2 associated X, apoptosis regulator (BAX) and BCL2 antagonist/killer 1 (BAK1) is also associated with the release of cytochrome c, somatic (CYCS), culminating in at least some degree of caspase 9 (CASP9) and CASP3 activation, which precipitates apoptotic cell death as it suppresses CGAS signaling. Whether activating apoptotic caspases to sublethal degrees in the absence of accrued MOMP may decelerate aging by limiting mtDNA-driven CGAS activation remains to be elucidated. IRF3 interferon regulatory factor 3.