Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response.

Abstract

Sepsis-induced myocardial dysfunction is associated with worse clinical outcomes and high mortality, but no effective therapeutic intervention has been explored, reinforcing the urgent need to develop innovative strategies. Mitochondrial dysfunction underlies the pathogenesis of sepsis-induced myocardial dysfunction. Herein, we assessed the effect of mitochondrial transplantation on sepsis-induced myocardial dysfunction in a rat model of cecal ligation and puncture (CLP)-induced sepsis. Male Wistar rats (n = 80, 12 weeks old, 250-300g) were divided into groups with/without CLP-induced sepsis receiving mitochondrial transplantation in single or two repetitive injections (1h or 1 and 7h post-CLP, respectively). Mitochondria were isolated from donor rats and injected intravenously (400µl of mitochondrial suspension containing 7.5 × 106 mitochondria/ml of respiration buffer) in recipient groups. Twenty-four hours post-operation, LDH and cTn-I levels, mitochondrial functional endpoints, expression of mitochondrial biogenesis (SIRT-1 and PGC-1α) and fission/fusion (Drp1/Mfn1 and Mfn2) genes, and inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels were evaluated. Survival was tested over 72h post-operation. Mitotherapy significantly improved 72-hours survival (P < .05) and decreased LDH and cTn-I levels (P < .01). It also restored mitochondrial function and expression of mitochondrial biogenesis and fusion genes, and decreased the expression of mitochondrial fission gene and the levels of inflammatory cytokines (P < .05 to P < .01). Mitotherapy with repetitive injections at 1 and 7h post-CLP provided noticeable mitoprotection in comparison with the group receiving mitotherapy at single injection. Mitotherapy improved mitochondrial function, biogenesis, and dynamic associated with SIRT-1/PGC-1α network and suppressed inflammatory response in CLP-induced sepsis model, therefore, offers a promising strategy to overcome life-threatening sepsis challenge.