Advances in mitochondria-nucleus crosstalk in septic cardiomyopathy

Sepsis-induced cardiomyopathy (SICM), a critical contributor to the high mortality rate associated with sepsis, involves complex pathophysiological mechanisms that remain incompletely elucidated. In recent years, dysregulation of bidirectional signaling communication between mitochondria and the nucleus has been recognized as a pivotal factor in the pathogenesis of SICM. The anterograde signaling pathways-including the PGC-1α/NRF1/NRF2 axis, SIRT3-mediated deacetylation, and TFAM-dependent mitochondrial DNA (mtDNA) maintenance-are suppressed by inflammation and metabolic disturbances. This suppression leads to impaired mitochondrial biogenesis and disrupted energy metabolism. Concurrently, within retrograde signaling pathways, molecular mediators such as reactive oxygen species (ROS), mtDNA, and calcium signaling activate pro-inflammatory and apoptotic pathways, notably NF-κB and cGAS-STING. This activation establishes a vicious cycle perpetuating inflammation and cellular damage. Although current targeted interventions aimed at modulating mitochondrial-nuclear crosstalk have demonstrated some efficacy in animal models, their clinical translation faces significant challenges. These include the dynamic nature of the disease, substantial interindividual variability, and difficulties in achieving targeted delivery. This review summarizes the mechanisms of mitochondrial-nuclear bidirectional signaling in SICM and explores potential therapeutic targets, aiming to provide novel insights for SICM treatment strategies.