mtROS-driven Sp1-dependent retrograde signaling promotes colorectal tumor progression via SIRT3-PAGM5 axis-governed mitochondrial homeostasis

Mitochondrial-nuclear communication is critical for maintaining mitochondrial integrity and cellular metabolic adaptation. While mitochondrial dysfunction triggers compensatory retrograde signaling, the molecular mechanisms underlying defect sensing and resolution remain poorly defined. Here, we demonstrated that mitochondrial reactive oxygen species (mtROS) trigger Sp1 stabilization and nuclear translocation, which directly activate transcription of the NAD+-dependent deacetylase SIRT3 through specific promoter binding, revealing a redox-sensitive regulatory axis controlling mitochondrial homeostasis. Mechanistically, SIRT3 sustains mitochondrial integrity through site-specific deacetylation (K141) of mitochondrial phosphoglycerate mutase 5 (PGAM5). Furthermore, SIRT3-mediated deacetylation of PGAM5 was instrumental in promoting Pink1/parkin-dependent mitophagy, thereby maintaining mitochondrial homeostasis. Alternatively, we identified the mitochondrial-nuclear retrograde signaling cascade comprising Sp1, SIRT3 and PGAM5 as a novel driver of colorectal tumorigenesis. Taken together, our findings reveal that mtROS act as pivotal signaling mediators linking mitochondrial perturbations to the nuclear transcriptional adaptation response via the Sp1-SIRT3-PGAM5 retrograde signaling axis. This retrograde signaling cascade enables adaptive transcriptional reprogramming to restore mitochondrial homeostasis, thereby endowing tumor cells with increased stress tolerance.