Journal article
Liver iron stores and effectors of ferroptosis are dependent on age and sex
Experimental physiology, Vol.109(12), pp.2046-2056
12/2024
DOI: 10.1113/EP092035
PMCID: PMC11607622
PMID: 39422319
Abstract
Ferroptosis is a form of cell death characterized by a pro-oxidative cellular milieu and iron-dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12- and 24-month-old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non-haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor-1. In female rats, the 24-month-old group had higher contents of thiobarbituric acid reactive substances compared with their 12-month-old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4-hydroxnonenal-modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis.Ferroptosis is a form of cell death characterized by a pro-oxidative cellular milieu and iron-dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12- and 24-month-old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non-haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor-1. In female rats, the 24-month-old group had higher contents of thiobarbituric acid reactive substances compared with their 12-month-old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4-hydroxnonenal-modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis.
Details
- Title: Subtitle
- Liver iron stores and effectors of ferroptosis are dependent on age and sex
- Creators
- Steven A Bloomer - Pennsylvania State UniversityBrett A WagnerGarry R Buettner - University of IowaKyle E Brown - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Experimental physiology, Vol.109(12), pp.2046-2056
- DOI
- 10.1113/EP092035
- PMID
- 39422319
- PMCID
- PMC11607622
- NLM abbreviation
- Exp Physiol
- ISSN
- 1469-445X
- eISSN
- 1469-445X
- Publisher
- WILEY
- Grant note
- NIH: P30 CA086862
We thank Dr Ryan Savitz at Neumann University for assistance with statistics. S.A.B. was supported by an internal grant from Penn State Abington. The ESR Facility at The University of Iowa was supported, in part, by NIH P30 CA086862.
- Language
- English
- Electronic publication date
- 10/18/2024
- Date published
- 12/2024
- Academic Unit
- Gastroenterology and Hepatology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984736749102771
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