Khan Muznah, Farooqi Sumera, Mitchell Katherine L, Chowdhury Subir Kumar Roy, Cabrera-Ayala Marian, Huang Jessica, Wallace Douglas C, Weiss Scott L
Critical Care Mitochondrial Unit, Nemours Biomedical Research, Nemours Children's Hospital, Wilmington, Delaware, USA.
Division of Critical Care, Department of Pediatrics, Nemours Children's Hospital, Wilmington, Delaware, USA.
FASEB J. 2024 Dec 15;38(23):e70228. doi: 10.1096/fj.202401379RR.
Sodium butyrate can reduce inflammation, but it is not known if butyrate can improve mitochondrial dysfunction during sepsis. We tested butyrate to prevent or reverse lipopolysaccharide (LPS)-induced mitochondrial dysfunction in murine kidney and liver. C57BL/6 mice were grouped as control (n = 9), intraperitoneal (IP) LPS (n = 8), pretreatment with IP butyrate 600 (n = 3) or 1200 mg/kg (n = 8) followed 2 h later by LPS, posttreatment with IP butyrate 600 (n = 3) or 1200 mg/kg (n = 7) 1 h after LPS, or butyrate 1200 mg/kg only (n = 8). Kidney and liver tissue were collected at 24 h to measure mitochondrial respiration, electron transport system (ETS) complex activity and subunit expression, and content (citrate synthase [CS] activity and mtDNA/nDNA). Kidney mitochondrial respiration was decreased after LPS compared to controls. Pretreatment with butyrate 1200 mg/kg increased kidney OXPHOS, ETS, ETS, and CIV respiration compared to LPS; posttreatment did not achieve significant increases except for OXPHOS. Liver mitochondrial respiration exhibited a similar pattern as in kidney, but differences were not significant. ETS complex and CS activity did not differ between groups, but CI and CII subunit expression trended higher with butyrate in kidney. Changes in mtDNA/nDNA followed a similar pattern as respiration in kidney and liver with a decrease after LPS that was not present with butyrate pretreatment. These data show that butyrate can prevent-but not significantly reverse-the LPS-induced decrease in kidney mitochondrial respiration without a clear effect in liver. Mitochondrial protection was not attributable to changes in ETS complex activity but may reflect maintenance of ETS subunit expression.
丁酸钠可减轻炎症，但尚不清楚丁酸盐是否能改善脓毒症期间的线粒体功能障碍。我们测试了丁酸盐对预防或逆转脂多糖（LPS）诱导的小鼠肾脏和肝脏线粒体功能障碍的作用。将C57BL/6小鼠分为对照组（n = 9）、腹腔注射LPS组（n = 8）、腹腔注射600（n = 3）或1200 mg/kg丁酸盐预处理组（n = 8），2小时后注射LPS，LPS注射1小时后腹腔注射600（n = 3）或1200 mg/kg丁酸盐后处理组（n = 7），或仅腹腔注射1200 mg/kg丁酸盐组（n = 8）。在24小时时收集肾脏和肝脏组织，以测量线粒体呼吸、电子传递系统（ETS）复合物活性和亚基表达以及含量（柠檬酸合酶[CS]活性和mtDNA/nDNA）。与对照组相比，LPS处理后肾脏线粒体呼吸降低。与LPS组相比，1200 mg/kg丁酸盐预处理可增加肾脏氧化磷酸化、ETS、ETS和细胞色素c氧化酶（CIV）呼吸；除氧化磷酸化外，后处理未实现显著增加。肝脏线粒体呼吸表现出与肾脏相似的模式，但差异不显著。各组之间ETS复合物和CS活性无差异，但肾脏中丁酸盐处理后CI和CII亚基表达呈上升趋势。肾脏和肝脏中mtDNA/nDNA的变化与呼吸模式相似，LPS处理后降低，丁酸盐预处理组则不存在这种情况。这些数据表明，丁酸盐可预防LPS诱导的肾脏线粒体呼吸降低，但不能显著逆转，对肝脏无明显作用。线粒体保护并非归因于ETS复合物活性的变化，可能反映了ETS亚基表达的维持。
