Mitochondrial Physiology Network 10.9: 107-108 (2005) - download pdf

The placental phenotype of a model of mitochondrial dysfunction in mice.

Sajida Malik, K Morten, N Ashley, P Field, R Boyd, J Poulton

Nuffield Department of Obstetrics & Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK. – sajida.malik@bnc.ox.ac.uk

    Maternal nutrition is known to affect fetal growth and development and by restricting protein intake studies have demonstrated several metabolic abnormalities leading to insulin resistance. Pups maintained on a low protein diet during lactation exhibit a lower growth weight and a reduced insulin response to glucose challenge. Proteome analysis has revealed altered expression of 70 proteins by fetal malnutrition including proteins related to mitochondrial energy transfer and glucose metabolism. Placental size is increased and a higher placental/birth weight ratio is seen in gestational diabetes. In mothers with anaemia produce larger placentas and in smoking mothers there is a reduced placental weight but increased ratio of placental weight to birthweight.

    A common variant in human mtDNA, at bp 16189, has been associated with type 2 diabetes, thinness at birth [1] and high placental weight in humans [2]. The T to C transition lies in the major non-coding region which contains control sequences for replication and transcription and is a bidirectional origin of replication [3] and produces a polyC tract.

    We have modeled the 16189 variant of mild mitochondrial dysfunction in mice by administering the mitochondrial inhibitor, zidovudine (AZT). This is a viral reverse transcriptase inhibitor used for the treatment of HIV infection.  One prominent side effect of AZT is mtDNA depletion as a result of inhibition of the mitochondrial gamma polymerase. We used four groups of mice: control (C), on either AZT (AZT), a low protein diet (LPD), or a combination of both (AZTLPD).

    We have previously shown that AZT reduces mtDNA copy number in liver of offspring (P=0.021). LPD decreased birthweight and litter size (P=0.012 and 0.01 respectively). A combination of AZT with LPD decreased birthweight and litter size and increased fasting glucose and insulin compared with untreated controls. Our preliminary data shows that LPD in combination with AZT significantly increases placental size (P=0.039).  We are now investigating this further by exploring placental histology and gene expression.

1. Casteels Ong K, Phillips D, Bendall H, Pembrey M (1999) Mitochondrial 16189 variant, maternal restraint of fetal growth and impaired glucose tolerance/type 2 diabetes Lancet 353: 1499-1500.

2. Morten KJ, Parker E, Bain SC, Cockington RA, Phillips DI, Poulton J (2004) A common mtDNA variant is associated with high placental weight and thinness at aged 20. Diabet. Med. 21 (suppl P14).

3. Yasukawa T, Yang MY, Jacobs HT, Holt IJ (2005) A bidirectional origin of replication maps to the major noncoding region of human mitochondrial DNA. Mol. Cell. 18: 651-662.