Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function
Iron is an essential co-factor for many cellular metabolic processes, and mitochondria are main sites of utilization. Iron accumulation promotes production of reactive oxygen species (ROS) via the catalytic activity of iron species. Herein, we investigated the consequences of dietary and genetic iro...
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MDPI AG
2021
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oai:doaj.org-article:ef4b4e66d0a84ee18a98a6038736a6872021-11-25T16:29:01ZDietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function10.3390/antiox101118182076-3921https://doaj.org/article/ef4b4e66d0a84ee18a98a6038736a6872021-11-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1818https://doaj.org/toc/2076-3921Iron is an essential co-factor for many cellular metabolic processes, and mitochondria are main sites of utilization. Iron accumulation promotes production of reactive oxygen species (ROS) via the catalytic activity of iron species. Herein, we investigated the consequences of dietary and genetic iron overload on mitochondrial function. C57BL/6N wildtype and <i>Hfe<sup>−/−</sup></i> mice, the latter a genetic hemochromatosis model, received either normal diet (ND) or high iron diet (HI) for two weeks. Liver mitochondrial respiration was measured using high-resolution respirometry along with analysis of expression of specific proteins and ROS production. HI promoted tissue iron accumulation and slightly affected mitochondrial function in wildtype mice. Hepatic mitochondrial function was impaired in <i>Hfe<sup>−/−</sup></i> mice on ND and HI. Compared to wildtype mice, <i>Hfe<sup>−/−</sup></i> mice on ND showed increased mitochondrial respiratory capacity. <i>Hfe<sup>−/−</sup></i> mice on HI showed very high liver iron levels, decreased mitochondrial respiratory capacity and increased ROS production associated with reduced mitochondrial aconitase activity. Although <i>Hfe<sup>−/−</sup></i> resulted in increased mitochondrial iron loading, the concentration of metabolically reactive cytoplasmic iron and mitochondrial density remained unchanged. Our data show multiple effects of dietary and genetic iron loading on mitochondrial function and linked metabolic pathways, providing an explanation for fatigue in iron-overloaded hemochromatosis patients, and suggests iron reduction therapy for improvement of mitochondrial function.Christine FischerChiara VolaniTimea KomlódiMarkus SeifertEgon DemetzLara Valente de SouzaKristina AuerVerena PetzerLaura von RaffayPatrizia MoserErich GnaigerGuenter WeissMDPI AGarticlehemochromatosisiron overloadreactive oxygen speciesmitochondriamitochondrial respirationliverTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1818, p 1818 (2021) |
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DOAJ |
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EN |
| topic |
hemochromatosis iron overload reactive oxygen species mitochondria mitochondrial respiration liver Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
hemochromatosis iron overload reactive oxygen species mitochondria mitochondrial respiration liver Therapeutics. Pharmacology RM1-950 Christine Fischer Chiara Volani Timea Komlódi Markus Seifert Egon Demetz Lara Valente de Souza Kristina Auer Verena Petzer Laura von Raffay Patrizia Moser Erich Gnaiger Guenter Weiss Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function |
| description |
Iron is an essential co-factor for many cellular metabolic processes, and mitochondria are main sites of utilization. Iron accumulation promotes production of reactive oxygen species (ROS) via the catalytic activity of iron species. Herein, we investigated the consequences of dietary and genetic iron overload on mitochondrial function. C57BL/6N wildtype and <i>Hfe<sup>−/−</sup></i> mice, the latter a genetic hemochromatosis model, received either normal diet (ND) or high iron diet (HI) for two weeks. Liver mitochondrial respiration was measured using high-resolution respirometry along with analysis of expression of specific proteins and ROS production. HI promoted tissue iron accumulation and slightly affected mitochondrial function in wildtype mice. Hepatic mitochondrial function was impaired in <i>Hfe<sup>−/−</sup></i> mice on ND and HI. Compared to wildtype mice, <i>Hfe<sup>−/−</sup></i> mice on ND showed increased mitochondrial respiratory capacity. <i>Hfe<sup>−/−</sup></i> mice on HI showed very high liver iron levels, decreased mitochondrial respiratory capacity and increased ROS production associated with reduced mitochondrial aconitase activity. Although <i>Hfe<sup>−/−</sup></i> resulted in increased mitochondrial iron loading, the concentration of metabolically reactive cytoplasmic iron and mitochondrial density remained unchanged. Our data show multiple effects of dietary and genetic iron loading on mitochondrial function and linked metabolic pathways, providing an explanation for fatigue in iron-overloaded hemochromatosis patients, and suggests iron reduction therapy for improvement of mitochondrial function. |
| format |
article |
| author |
Christine Fischer Chiara Volani Timea Komlódi Markus Seifert Egon Demetz Lara Valente de Souza Kristina Auer Verena Petzer Laura von Raffay Patrizia Moser Erich Gnaiger Guenter Weiss |
| author_facet |
Christine Fischer Chiara Volani Timea Komlódi Markus Seifert Egon Demetz Lara Valente de Souza Kristina Auer Verena Petzer Laura von Raffay Patrizia Moser Erich Gnaiger Guenter Weiss |
| author_sort |
Christine Fischer |
| title |
Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function |
| title_short |
Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function |
| title_full |
Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function |
| title_fullStr |
Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function |
| title_full_unstemmed |
Dietary Iron Overload and <i>Hfe<sup>−/−</sup></i> Related Hemochromatosis Alter Hepatic Mitochondrial Function |
| title_sort |
dietary iron overload and <i>hfe<sup>−/−</sup></i> related hemochromatosis alter hepatic mitochondrial function |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/ef4b4e66d0a84ee18a98a6038736a687 |
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