Introduction: Persistence of low mitochondrial respiration in peripheral blood mononuclear cells (PBMC) is linked to prolonged organ dysfunction and inflammation in pediatric sepsis. This suggests that mechanisms impeding mitochondrial recovery may slow clinical progress. We hypothesized that persistently low PBMC mitochondrial respiration is associated with insufficient mitochondrial biogenesis and mitophagy that allows ongoing cytosolic leak of mitochondrial DNA (mtDNA) to sustain inflammation. Methods: We studied 90 patients < 18 years with sepsis over 4 years. Blood was collected within 48 hrs (T1) and days 3 (T2), 5 (T3), and 7 (T4). Mitochondrial respiration was measured in PBMC as spare respiratory capacity (SRC) to estimate bioenergetic reserve. Persistently low SRC was defined as < 10th percentile of control values by T2 based on our prior studies. Mitochondrial biogenesis and mitophagy were measured as TFAM and Parkin gene expression, respectively, using rtPCR. Mitochondrial content was measured in whole cells and cytosol fraction as mtDNA normalized to nDNA using qPCR. Plasma IL1β and IL6 were measured using ELISA. Data for patients with versus without persistently low SRC were compared with mixed effects linear regression using log-transformed values. Results: Of sepsis patients, 38% had persistently low SRC. Patients with or without persistently low SRC did not differ in median age (11 vs 10 yrs, p=0.47) or PRISM score (9 vs 11, p=0.2) but did have fewer organ failure-free days (16 vs 21, p< 0.01). Patients with persistently low SRC had lower TFAM gene expression at all timepoints (all p< 0.05) and no rise in TFAM (Ptrend=0.30 vs < 0.05) compared to those without persistently low SRC. Parkin expression was lower at T1 (p< 0.05) only. Whole cell mtDNA/nDNA was lower in persistently low SRC group at T2 (p< 0.01) but not other times. Cytosolic mtDNA/nDNA rose only in patients with persistently low SRC, though not significantly (Ptrend =0.09). IL1β and IL6 remained higher over time in patients with persistently low SRC. Conclusions: Persistently low PBMC mitochondrial respiration was associated with less mitochondrial biogenesis, a trend toward higher cytosolic mtDNA, and sustained inflammation. Stimulation of mitochondrial quality control may be a strategy to promote recovery in pediatric sepsis.
Weiss et al. (Sun,) studied this question.