TRANSFERRIN IRON-LOBE DISTRIBUTION AND POST-TRANSLATIONAL MODIFICATIONS IN HEMOCHROMATOSIS
Hereditary Hemochromatosis (HH) is a widespread autosomal recessive disorder in Northern European populations. It is characterized by high iron absorption, systemic iron overload, elevated iron stores, and increased oxidative stress. The iron transport protein Transferrin (Tf) is necessary for cellular iron internalization, and systemic distribution. Post Translational Modifications (PTMS) have been identified in Tf and have the potential to modify its function and iron-binding capacity in a physiologically relevant manner.
This study focused on assessing asymmetrical iron lobe distribution in Tf and investigating potential changes in HH patients compared to healthy individuals. We also aimed at identifying PTMs in Tf binding sites and their interplay with iron lobe distribution. Serum samples from p.C282Y homozygous HH patients, undergoing phlebotomy and samples from healthy blood donors were analysed using Urea-gel electrophoresis and Mass Spectrometry-Based Proteomics to study iron lobe distribution and Tf modifications.
HH patients exhibited significantly higher Tf-Fe2 levels (65%) and lower Apo-Tf levels (11%) compared to healthy individuals (12% Tf-Fe2, 46% Apo-Tf). It was also found that patients undergoing intensive treatment presented significantly lower Tf-FeN levels (7.5%) when compared to controls (20%). Tf PTMs were identified which might impact Tf function and alter its iron-binding dynamics and lobe distribution.
These findings might help to enlighten how PTMs can potentially compromise Tf iron-binding capacity. However, a higher understanding of Tf biochemistry is needed to explain differential clinical outcomes and disease-specific patterns of iron deposition.
Funding: The work was financially supported by the eQuaNTI project (2022.06328.PTDC), funded by FCT/MCTES through national funds.
This study focused on assessing asymmetrical iron lobe distribution in Tf and investigating potential changes in HH patients compared to healthy individuals. We also aimed at identifying PTMs in Tf binding sites and their interplay with iron lobe distribution. Serum samples from p.C282Y homozygous HH patients, undergoing phlebotomy and samples from healthy blood donors were analysed using Urea-gel electrophoresis and Mass Spectrometry-Based Proteomics to study iron lobe distribution and Tf modifications.
HH patients exhibited significantly higher Tf-Fe2 levels (65%) and lower Apo-Tf levels (11%) compared to healthy individuals (12% Tf-Fe2, 46% Apo-Tf). It was also found that patients undergoing intensive treatment presented significantly lower Tf-FeN levels (7.5%) when compared to controls (20%). Tf PTMs were identified which might impact Tf function and alter its iron-binding dynamics and lobe distribution.
These findings might help to enlighten how PTMs can potentially compromise Tf iron-binding capacity. However, a higher understanding of Tf biochemistry is needed to explain differential clinical outcomes and disease-specific patterns of iron deposition.
Funding: The work was financially supported by the eQuaNTI project (2022.06328.PTDC), funded by FCT/MCTES through national funds.