Rethinking post-sepsis syndrome: linking cellular dysfunction to the clinical picture

Abstract

Post-sepsis syndrome (PSS) encompasses a range of long-term complications, including immune dysregulation, chronic inflammation, and neuromuscular impairment, that persist beyond the resolution of the acute septic episode. While these clinical phenotypes are increasingly recognized, the underlying molecular mechanisms remain incompletely defined. Mitochondrial dysfunction, particularly in the form of persistent mitochondrial senescence, is emerging as a potential unifying factor driving multiple PSS trajectories. Accumulating evidence suggests that damaged mitochondria not only lose their bioenergetic capacity but also actively contribute to chronic immune and inflammatory signalling. Based on this, we propose a dual-intervention strategy (“mitochondrial flush”) which involves the coordinated elimination of senescent mitochondria and stimulation of mitochondrial biogenesis. The regenerative component, supported by established preclinical research on Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α) activation, represents a partially developed therapeutic arm, while the selective clearance of dysfunctional mitochondria remains an area of active investigation. This concept raises important questions regarding regenerative capacity, therapeutic timing, and cellular resilience following critical illness. We further propose a working definition of PSS as a state of persistent mitochondrial dysfunction, possibly driven by ongoing oxidative stress, which may underlie a broader range of clinical phenotypes than currently recognized. A deeper understanding of mitochondrial quality control may offer a new therapeutic framework for reversing the chronic physiological decline observed in sepsis survivors.