Abnormal mitochondrial fusion–fission balance contributes to the progression of experimental sepsis

Abstract

Sepsis-associated multiple organ failure is a major cause of mortality characterized by a massive increase of reactive oxygen and nitrogen species (ROS/RNS) and mitochondrial dysfunction. Despite intensive research, determining events in the progression or reversal of the disease are incompletely understood. Herein, we studied two prototype sepsis models: endotoxemia and cecal ligation and puncture (CLP)-which showed very different lethality rates (2.5% and 67%, respectively)-, evaluated iNOS, ROS and respiratory chain activity, and investigated mitochondrial biogenesis and dynamics, as possible processes involved in sepsis outcome. Endotoxemia and CLP showed different iNOS, ROS/RNS, and complex activities time-courses. Moreover, these alterations reverted after 24-h endotoxemia but not after CLP. Mitochondrial biogenesis was not elicited during the first 24 h in either model but instead, 50% mtDNA depletion was observed. Mitochondrial fusion and fission were evaluated using real-time PCR of mitofusin-2 (Mfn2), dynamin-related protein-1 (Drp1), and using electron microscopy. During endotoxemia, we observed a decrease of Mfn2-mRNA levels at 4-6 h, and an increase of mitochondrial fragmentation at 6 h. These parameters reverted at 24 h. In contrast, CLP showed not only decreased Mfn2-mRNA levels at 12-18 h but also increased Drp1-mRNA levels at 4 h, and enhanced and sustained mitochondrial fragmentation. The in vivo pretreatment with mdivi-1 (Drp1 inhibitor) significantly attenuated mitochondrial dysfunction and apoptosis in CLP. Therefore, abnormal fusion-to-fission balance, probably evoked by ROS/RNS secondary to iNOS induction, contributes to the progression of sepsis. Pharmacological targeting of Drp1 may be a potential novel therapeutic tool for sepsis.

Mitochondrial Function in Sepsis

“…In a preclinical animal model of sepsis (CLP) there was an abnormal balance of fission and fusion responses thought to contribute to cellular injury and apoptosis. The in vivo pretreatment with mdivi-1 (Drp1 inhibitor) significantly attenuated mitochondrial dysfunction and apoptosis in CLP (52). …”

Mitochondrial fission – a drug target for cytoprotection or cytodestruction?

“…) and liver (Gonzalez et al. ), where in vivo administration of Mdivi‐1 conferred cytoprotection of important cell types in these organs (i.e., retinal ganglion cells, renal tubular epithelial cells, and hepatocytes, respectively). Despite these promising results, many challenges (as discussed in the next section) await before Mdivi‐1 might be suitable for patients.…”

Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system

“…Perturbation of the mitochondrial fission-fusion balance can aggravate ROS-induced tissue injury [50]. Accordingly, we found that increased accumulation of Opa1-S by AZT caused mitochondrial fragmentation (Fig.…”