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Sex-specific Changes in Neonatal Cardiac Mitochondria in Response to Perinatal Iron Deficiency

  • Author / Creator
    Holody, Claudia D
  • Introduction: Iron deficiency (ID) during gestation has been shown to alter growth and developmental trajectories, consequentially increasing the risk of long-term cardiovascular dysfunction in offspring. The heart becomes energetically dependent on mitochondria soon after birth and disturbances in energy metabolism could impact cardiac development. Given that iron is essential for oxygen transport and an important component of the electron transport system, we hypothesized that perinatal ID would alter cardiac mitochondrial function in the neonatal period. Objectives: In hearts of neonatal control and iron-deficient offspring, we sought to (1) perform untargeted proteomics analysis; (2) assess changes in mitochondrial function and reactive oxygen species generation, and (3) explore the mechanisms of iron metabolism underlying these changes. Methods: Female rats were fed an iron-restricted or an iron-replete diet before and during pregnancy. Hearts from neonatal male and female pups underwent quantitative shotgun proteomics analysis. Mitochondrial content and function were assessed by citrate synthase activity and high-resolution respirometry, respectively. Superoxide levels were assessed using dihydroethidium fluorescence. Antioxidant and iron metabolism genes were assessed by RT-qPCR. The effects of ID and postnatal day (PD) were analyzed by fitting a mixed-effects model. Results: Hemoglobin levels were reduced in ID pups at PD0 and PD14 but recovered by PD28. Body weights of ID pups were reduced at all time points, while heart weights (normalized to body weight) were increased. Shotgun proteomics revealed upregulation of mitochondrion organization proteins in ID male hearts. In ID male hearts only, the mitochondrial content, shown by the citrate synthase activity, was increased by 25% while the mitochondrial respiration through the NADH-pathway, succinate-pathway, and FAO-pathway, expressed per citrate synthase activity units, was reduced by up to 50%. ID did not change superoxide or antioxidant enzyme mRNA levels in either sex. Transferrin receptor-1 mRNA was increased in ID females; upregulation of this protein was confirmed by proteomics at PD0. Conclusions: Although male and female neonates experience a similar insult with maternal iron-restriction, only male hearts showed reduced mitochondrial efficiency and compensation by increased mitochondrial content. Lack of changes in other parameters indicate that mitochondria in male ID hearts are likely functional but may have an abnormal protein composition. Further, females may have a greater capacity to prioritize iron for the heart by increasing iron import during ID.

  • Subjects / Keywords
  • Graduation date
    Fall 2023
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-tcr7-k704
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.