Beyond the nucleus: the ATM-CHEK2 axis senses mtROS to orchestrate mitophagy

Mitochondrial reactive oxygen species (mtROS) are typically viewed as harmful byproducts of stress. However, our recent study establishes their fundamental role as essential signaling molecules that activate a protective adaptive response. We discovered that mtROS serve as the specific trigger to activate the ATM-CHEK2/CHK2 DNA damage response pathway, which in turn coordinates the key steps of PINK1-PRKN/Parkin-dependent mitophagy. Upon activation by mtROS, CHEK2 phosphorylates ATAD3A to initiate PINK1 import arrest, OPTN to enhance cargo recognition, and BECN1 (beclin 1) to promote autophagosome formation. This work reveals a novel mtROS-driven signaling cascade, expanding the function of the ATM-CHEK2 pathway beyond the nucleus and positioning it as a central integrator of cellular homeostasis by responding to both genomic and mitochondrial stress.