University of Manchester
Developmental Programming of Mitochondria by Fetal Hypoxia
Lead researcher - Dr Kerri Smith
An inadequate prenatal environment is known to have long-lasting consequences on the heart. Specifically, reductions in fetal oxygen supply have been associated with changes to cardiac structure and function, which can increase the risk of heart disease.
Healthy mitochondria are crucial for providing the energy required for proper heart function. Mitochondria are disproportionately affected by low oxygen (hypoxia), with hypoxic conditions leading to reductions in ATP production and increases in release of reactive oxygen species.
How does mitochondrial programming affect cardiac function?
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We are researching the effects of developmental hypoxia on mitochondrial function, in both the fetal and adult heart. In particular we want to assess if developmental hypoxia has any effect on the mitochondrial permeability transition pore (MPTP), which is a crucial mitochondrial component that regulates cell death and is involved in ischemia-reperfusion injury. Having a greater understanding of what causes increased ischemia-reperfusion injury is crucial, as ischemia-reperfusion injury can occur in a variety of clinical conditions including myocardial infarction, surgery and transplantation.
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The techniques we use to study this include: microrespirometry, calcium retention capacity assays, Western blotting, qPCR, Langendorff preparation, epicardial fluorescence imaging, oxidative stress assays etc.
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So far, we have shown that animals from hypoxic pregnancies possess mitochondria with lower calcium buffering capabilities, and increased abundance of MPTP components. These mitochondria also produce more reactive oxygen species, which likely contributes towards MPTP opening. Overall these results are expected to contribute to the phenotype of increased ischemia-reperfusion injury commonly seen following developmental hypoxia.
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Future research could include maternal antioxidant administration to see whether this reverses the phenotype observed.
Relevant Papers
Hellgren KT, Premanandhan H, Quinn CJ, Trafford AW, Galli GLJ. Sex-dependent effects of developmental hypoxia on cardiac mitochondria from adult murine offspring. Free Radic Biol Med. 2021 Jan:162:490-499. doi: 10.1016/j.freeradbiomed.2020.11.004. Epub 2020 Nov 10.
Xue Q, Zhang L. Prenatal hypoxia causes a sex-dependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring: role of protein kinase C. J Pharmacol Exp Ther. 2009 Aug; 330(2): 624–632. Published online 2009 May 26. doi: 10.1124/jpet.109.153239.
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