skip to primary navigationskip to content
 

Mitochondrial function during pregnancy in a model of abnormal folate metabolism

Mitochondrial function during pregnancy in a model of abnormal folate metabolism

 

Supervisors: Dr Erica Watson and Dr Andrew Murray

 

It is well known that maternal intake of the vitamin folate (folic acid) reduces the risk of fetal neural tube defects. Dietary folate deficiency is also attributed to other pregnancy disorders, such as intrauterine growth restriction, preeclampsia, and placental abruption. Folate metabolism is required for DNA and amino acid synthesis, and methylation in the cell (e.g., of DNA, histones, and RNA). The Watson lab has derived a mouse model of abnormal folate metabolism by mutating the Mtrr gene. Mtrr deficiency disrupts the progression of folate metabolism leading to global DNA hypomethylation and epigenetic instability associated with gene misexpression.

 

Remarkably, the Mtrr mouse line is a model of transgenerational inheritance particularly though the maternal lineage. This means that when either maternal grandparent (generation I) is a carrier for the Mtrr mutation, their wildtype grandprogeny (generation III) are at risk for epigenetic instability and a wide spectrum of phenotypes. These include growth defects, which have been attributed to an atypical uterine environment in generation II, and congenital malformations, which are likely caused by the inheritance of an abnormal epigenetic factor via the germline. However, the epigenetic mechanism in each case is not well understood.

 

Folate metabolism is compartmentalized in the cytosol and mitochondria. However, whether Mtrr deficiency disrupts normal mitochondrial function and whether mitochondrial dysfunction is, at least in part, responsible for the phenotypes observed in the Mtrr model has not yet been considered. This project will explore mitochondrial function in specific tissues from non-pregnant and pregnant females that are either homozygous mutant for the Mtrr mutation or are wildtype and derived from an Mtrr-deficient parent or grandparent. Mitochondrial status will be linked to phenotypic outcome in litters that result. Genetic and epigenetic stability of mitochondrial genes will be assessed. Other metabolic and physiological indices will be measured. Altogether, assessing mitochondrial function in the Mtrr model will be important when exploring po ssible maternal environment effects on development and a possible epigenetic factor inherited via oocytes.

 

For more information, please do not hesitate to contact us via email:

edw23@cam.ac.uk or ajm267@cam.ac.uk

 

Relevant References:

 

  1. Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda MC, Snyder FF, Gravel RA, Cross JC, and Watson ED. (2013) Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155, 81-93.

 

  1. Watson ED and Rakoczy J. (2016) Fat eggs shape offspring health. Nature Genetics 48(5), 478-9.

 

  1. Blake GET and Watson ED. (2016) Unravelling the complex mechanisms of transgenerational epigenetic inheritance. Current Opinion in Chemical Biology 33, 101-107.

 

  1. Colleoni F, Padmanabhan N, Yung HW, Watson ED, Cetin I, Tissot van Patot MC, Burton GJ, and Murray AJ. (2013) Suppression of mitochondrial election transport chair function in the hypoxic human placenta: a role for miRNA-20 and protein synthesis inhibition. PLoS One 8(1): e55194.