Human Reproduction, Vol. 15, No. suppl_2, pp. 160-172, 2000
© 2000 European Society of Human Reproduction and Embryology
Chromosomal non-disjunction in human oocytes: is there a mitochondrial connection?
1 Department of Neurology, Columbia University Bronx, NY 10461, USA 2 Department of Genetics and Development, Columbia University Bronx, NY 10461, USA 3 Department of Obstetrics and Gynecology, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY 10461, USA 4 Armed Forces Radiobiology Research Institute Bethesda, MD 20889–5603, USA 5 Department of Pediatrics, Columbia University 630 West 168th Street, New York, NY 10032, USA
Correspondence: 6To whom correspondence should be addressed at: Department of Neurology, Room 4–431 Columbia University, 630 West 168th Street, New York, NY 10032, USA. E-mail: eas3{at}columbia.edu
The frequency of chromosome abnormalities due to non-disjunction of maternal chromosomes during meiosis is a function of age, with a sharp increase in the slope of the trisomy-age curve between the ages of 30 and 40 years. The basis of this increase, which is a major cause of birth defects, is unknown at present. In recent years, mutations in mitochondrial (mt) DNA have been associated with a growing number of disorders, including those associated with spontaneous deletions of mtDNA (
mtDNAs). Intriguingly, these pathogenic mtDNAs, which are present at extremely high levels in certain patients, are also present at extremely low levels (detectable only by polymerase chain reaction) in normal individuals. The proportion of such mtDNAs in normal muscle is a function of age; the shape of this curve is exponential, with the accelerating part of the curve beginning at 
30–40 years. We postulate that, as well as muscle and brain, a similar time-dependent accumulation of mtDNAs also occurs in normal oocytes. Since mtDNAs are functionally inactive, an accumulation of such aberrant genomes could eventually compromise ATP-dependent energy-utilization in these cells. Furthermore, these deficiencies would also affect the function of the somatic follicular cells that surround, and secrete important paracrine factors to, the oocyte. If there is indeed an age-associated relationship between mtDNAs and oocyte age, perhaps errors in meiosis (which is almost certainly an energy, and ATP, dependent process) are related to mutations in mtDNA (primarily deletions, but perhaps point mutations as well) in oocytes and/or the surrounding somatic cells, which result in deficiencies in both mitochondrial function in general and oxidative energy metabolism in particular. This hypothesis would explain many of the non-Mendelian features associated with maternal age-related trisomies, e.g. Down's syndrome.
Key words: ageing/Down's syndrome/meiosis/mitochondrial disease/mitochondrial DNA
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