Mitochondrial Dysfunction, Bioenergetic Impairment, and Metabolic Down-Regulation in Sepsis

Abstract

Mitochondrial dysfunction is thought to play an important role in the pathogenesis of many different disease states. It has been proposed that an acquired defect in oxidative phosphorylation prevents cells from using molecular oxygen for adenosine triphosphate production and potentially causes sepsis-induced organ dysfunction. This concept, termed cytopathic hypoxia, however, has been difficult to prove because impaired oxidative phosphorylation has never been shown to cause sepsis-induced organ failure or to be a reversible phenomenon. Presented here is are view of oxidative phosphorylation, evidence of defective electron-transport-chain function in the heart and other organ systems during sepsis, and support for a link between mitochondrial dysfunction and pathologic metabolic down-regulation.

Peritoneal Inflammation in Pigs is Associated with Early Mitochondrial Dysfunction in Liver and Kidney

“…Sham sham-operated pigs, Peri pigs subjected to peritoneal inflammation. *p<0.05; **p<0.01. electron transfer chain dysfunction, e.g., by loss of cytochrome c as shown by Levy et al [36,37]. The significant respiratory rate decrease in states 2 and 4 indicates that there is no damage to the inner mitochondrial membrane.…”

Endothelial Dysfunction Is a Potential Contributor to Multiple Organ Failure and Mortality in Aged Mice Subjected to Septic Shock: Preclinical Studies in a Murine Model of Cecal Ligation and Puncture

“…On the basis of the aforementioned studies, we also hypothesize that the exacerbation of ROS/RNS-mediated responses and endothelial dysfunction are key contributors to the development of mitochondrial dysfunction demonstrated in the current study. According to multiple preclinical and clinical studies, mitochondrial dysfunction (or 'cytopathic hypoxia') is a significant contributor to organ dysfunction and mortality in various forms of critical illness [65][66][67]; based on the current data, we hypothesize that a suppression of endothelial NO production may be one of the upstream/proximate causes of this defect. It was also interesting to note that eNOS deficiency, as well as aging, both produced a comparable degree of 'baseline' suppression of mitochondrial function.…”

Mitochondrial Antioxidants Alleviate Oxidative and Nitrosative Stress in a Cellular Model of Sepsis

“…Patients under septic shock have been shown to display significant oxidative stress, manifested by increased levels of lipid peroxides, decreased antioxidant capacity and altered mitochondrial redox state (6)(7)(8)(9). Moreover, post-mortem analyses of livers from patients with sepsis has revealed the presence of hypertrophic mitochondria with depressed Complex I and Complex IV activity (10).…”