Mitochondrial quality-control uncoupling in sepsis: a missing link to persistent immune hyporesponsiveness

Sepsis imposes competing demands for antimicrobial activity and organelle maintenance. Mitochondrial recovery requires coordinated damage containment, selective removal, lysosomal degradation and recycling, and functional replacement. We define mitochondrial quality-control uncoupling as a mismatch among these processes. When damage outpaces completed clearance, dysfunctional mitochondria retain redox and danger-signaling activity. When removal outpaces replacement, mitochondrial mass and spare respiratory capacity decline. Incomplete lysosomal processing can combine both phenotypes by removing mitochondria from the functional network while retaining undegraded cargo. Immune cells may therefore remain viable yet fail to increase metabolic and biosynthetic output during renewed challenge. Inhibitory immune signaling can further restrict substrate use and mitochondrial rebuilding, reinforcing mitochondrial and immune dysfunction. This framework reconciles divergent observations on mitophagy and explains how inflammation can coexist with ineffective host defense. We define state-matched longitudinal phenotyping as repeated, cell-type-specific assessment of damage burden, clearance completion, respiratory reserve and immune function over time. Such phenotyping could guide interventions toward the dominant defect rather than indiscriminately activating a single pathway.