Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

Abstract

Mitochondrial dysfunction is increasingly recognized as an accomplice in most of the common human diseases including cancer, neurodegeneration, diabetes, ischemia/reperfusion injury as seen in myocardial infarction and stroke, and sepsis. Inflammatory conditions, both acute and chronic, have recently been shown to affect mitochondrial function. We here discuss the role of oxidative phosphorylation (OxPhos), focusing on acute inflammatory conditions, in particular sepsis and experimental sepsis models. We discuss mitochondrial alterations, specifically suppression of oxidative metabolism and the role of mitochondrial reactive oxygen species in disease pathology. Several signaling pathways including metabolic, proliferative, and cytokine signaling affect mitochondrial function and appear to be important in inflammatory disease conditions. Cytochrome c oxidase (COX) and cytochrome c, the latter of which plays a central role in apoptosis in addition to mitochondrial respiration, serve as examples for the entire OxPhos system since they have been studied in more detail with respect to cell signaling. We propose a model in which inflammatory signaling leads to changes in the phosphorylation state of mitochondrial proteins, including Tyr304 phosphorylation of COX catalytic subunit I. This results in inhibition of OxPhos, a reduction of the mitochondrial membrane potential, and consequently a lack of energy, which can cause organ failure and death as seen in septic patients.

Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons

“…In addition, it has been suggested that inflammatory signaling leads to changes in the phosphorylation state of mitochondrial proteins, which results in an inhibition of respiratory chain activity, a reduction of the mitochondrial membrane potential, and consequently a lack of energy production. 56 In this regard, the effect of KU-596 to improve mtBE might be partially attributed to its effects in ameliorating inflammatory signaling in the sensory neurons.…”

SC-III3, a novel scopoletin derivative, induces autophagy of human hepatoma HepG2 cells through AMPK/mTOR signaling pathway by acting on mitochondria

“…3C). The results indicated that SC-III3 could destruct the electron transport chain, the major source of cellular ATP [24]. Therefore, we measured the ATP content in HepG2 cells treated with SC-III3.…”

The subunit composition and function of mammalian cytochrome c oxidase

“…The same site was identified in liver tissue after stimulation of the inflammatory pathway using TNFα followed by strong COX inhibition, decreased mitochondrial membrane potential, and significantly reduced ATP levels (Samavati et al, 2008). It was proposed that inflammatory signaling leads to phosphorylation of mitochondrial proteins, including Tyr304 of COX subunit I, leading to a lack of energy, which can cause organ failure and death as seen in septic patients (Lee and Hüttemann, 2014).…”