Brain Mitochondrial Dysfunction in a Cecal Slurry Sepsis Mouse Model of Neurobehavioral Morbidity

Introduction: Sepsis survivors commonly suffer long-term neurobehavioral morbidity. Mitochondrial dysfunction is linked to acute organ dysfunction during sepsis, but it is unknown if similar pathobiology contributes to neurobehavioral morbidity after sepsis. We hypothesized that mitochondrial dysfunction would be evident in the brain during and after sepsis in a mouse model of sepsis-induced neurobehavioral morbidity.


Methods: We randomized 7-8-week-old C57BL/6 mice to intraperitoneal injection of 1500 mg/kg cecal slurry for sepsis or saline for controls. Mice were euthanized at either 48 hours (acute) or 2 weeks (survival) post-injection. All sepsis and control mice were treated with ceftriaxone and buprenorphine to avoid confounding. Survival mice underwent neurobehavioral testing prior to euthanasia. Homogenized whole brain tissue was used to measure mitochondrial respiration (in pmol/sec/mg tissue) using high-resolution respirometry and electron transport system (ETS) enzymatic activity (in nmol/min/mg tissue) using spectrophotometry. Data are reported as mean ±SD and compared using unpaired t-tests.


Results: Thirty-one mice were included—acute sepsis (n=10), acute controls (n=8), survival sepsis (n=7), and survival controls (n=6). Two acute sepsis mice died prior to euthanasia and were excluded. Sepsis mice had higher murine sepsis scores than controls (8 ±6 vs 0 ±0, p< 0.001). Survival sepsis mice trended toward worse anxiety and memory than controls. During acute sepsis, brain mitochondrial respiration was increased through ETS complex II (88 ±8 vs 66 ±7, p=0.05) and complex IV (167 ±11 vs 123 ±11, p=0.02) compared to controls. Mice surviving sepsis had no significant differences in brain mitochondrial respiration, although complex IV respiration was numerically lower than controls (110 ±11 vs 142 ±17, p=0.14). Enzymatic activity of complex IV was not different during acute sepsis but was significantly lower in mice surviving sepsis compared to controls (211 ±74 vs 505 ±29, p=0.02).


Conclusions: In a mouse model of sepsis-induced neurobehavioral morbidity, mitochondrial respiration was not evident in whole brain homogenates during sepsis but mitochondrial complex IV dysfunction was evident after sepsis. Further study of mitochondrial dysfunction as a mechanism of morbidity after sepsis is warranted.