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Type of publication: Diploma Thesis
Type of document:

Year: 2009

Authors: Cronstedt-Fell, A

Title: The effect of the hemoxygenase modulating porphyrins, hemin (inducer) and Zn-protoporphyrin (inhibitor), on mitochondrial function and their impact on the induction of endoplasmic reticulum-stress.

Source: Diplomarbeit, Vet. Med. Univ. Wien, pp. 38.


Advisor(s):

Duvigneau Catharina

Kozlov, Andrey

Reviewer(s):
Gemeiner Manfred


Graduation date: 20.08.09


Abstract:
Heme oxygenase 1 (HO-1) is the inducible isoform of the heme degrading enzymes. This reaction yields ferrous iron, carbon monoxide (CO) and biliverdin (BV), which is rapidly converted into bilirubin (BR). HO-1 is induced upon cell stress and considered to confer cytoprotection by different means. On the one hand HO-1 removes excessive heme, a pro- oxidative compound. On the other hand the reaction products CO and BV/BR have been shown to protect cells against apoptosis and oxidative stress. But the third product free iron is a known prooxidative agent as well. Consequently, the effects of HO activity on subcellular level can be either beneficial or harmful. However, very little is known about the effects of the HO system on functions of subcellular structures, such as mitochondria and the endoplasmic reticulum (ER). Therefore we investigated the effect of hemin (inducer of HO-1) and the substrate analogue Zn-protoporphyrin (an inhibitor of HO, ZnPP) on mitochondrial function. We studied the effects of these two compounds on isolated mitochondria and on mitochondria within the cellular context (rat hepatocytes: BBR 3a cells). Using high resolution respirometry we found that hemin, but not ZnPP, inhibited the respiration of isolated mitochondria. However, confocal microscopy revealed that mitochondrial function within the cellular context was not compromised by hemin. While ZnPP had no effect by itself, the simultaneous administration of hemin plus ZnPP compromised mitochondrial function within the cells and resulted in subsequent ER stress. This was evidenced by real-time PCR showing an increased splicing of X-box- binding protein-1 mRNA, which is a marker of ER stress. Thus we conclude that HO-1 is able to protect mitochondria against toxic effects of hemin, possibly via the HO reaction products BV/BR.


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