A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction

Abstract

Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe 2 þ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-a and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8 h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron (ferritin) and the export of iron out of the cells (ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.

Kinetics and Specificity of Feline Leukemia Virus Subgroup C Receptor (FLVCR) Export Function and Its Dependence on Hemopexin

“…Because FLVCR-deleted mice develop iron overload in liver and duodenum, as well as tissue macrophages, by 12 weeks (2) and accumulate iron in renal tubular cells by 9 months, 5 heme trafficking via FLVCR at these sites likely contributes to iron homeostasis (3). Heme export via FLVCR may also provide protection from heme or ferrous iron toxicities in liver and brain, as our observations support emerging hypotheses concerning hepatic (45) and neuronal (46,47) injury.…”

Criteria for Early Identification of Aceruloplasminemia

“…Recently, it was reported that oxidative stress plays one of the pivotal roles in central nervous system damage in aceruloplasminemia (11). If oxidative stress is one of the major causes of cell damage in aceruloplasminemia, another way to treat it may be to reduce oxidative stress using a drug such as deferiprone (12).…”

A multianalyte fluorescent carbon dots sensing system constructed based on specific recognition of Fe(iii) ions

“…Iron overload and deciency can disturb cellular homeostasis and give rise to various diseases resulting from biological disorders, such as anemia, 6 dysfunction of kidney 7,8 and liver, 9,10 arthritis, Alzheimer's disease, 11,12 heart failure, diabetes, and cancer. 13,14 Therefore, the determination of Fe(III) is of great signicance for early diagnoses of these diseases.…”