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Neutral Mitochondrial Heteroplasmy Alters Physiological Function in Mice¹

Division of Reproductive Endocrinology and Infertility, Departments of Obstetrics and Gynecology and Physiology, University of Toronto, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5

ABSTRACT

Cytoplasmic transfer is an assisted reproductive technique that involves the infusion of ooplasm from a donor oocyte into a recipient oocyte of inferior developmental competence. Although this technique has shown some success for couples with recurrent in vitro fertilization failure, it results in mitochondrial heteroplasmy in the offspring, defined as the presence of two different mitochondrial genomes in the same individual. Because the long-term health consequences of mitochondrial heteroplasmy are unknown, there is a need for appropriate animal models to evaluate any physiological changes of dual mtDNA genotypes. This longitudinal study was designed as a preliminary screen of basic physiological functions for heteroplasmic mice (NZB mtDNA on a BALB/cByJ background). The mice were tested for cardiovascular and metabolic function, hematological parameters, body mass analysis, ovarian reserve, and tissue histologic abnormalities over a period of 15 mo. Heteroplasmic mice developed systemic hypertension that corrected over time and was accompanied by cardiac changes consistent with pulmonary hypertension. In addition, heteroplasmic animals had increased body mass and fat mass compared with controls at all ages. Finally, these animals had abnormalities in electrolytes and hematological parameters. Our findings suggest that there are significant physiological differences between heteroplasmic and control mice. Because ooplasm transfer appears to be consistently associated with mitochondrial heteroplasmy, children conceived through ooplasm transfer should be closely followed to determine if they are at risk for any health problems.

assisted reproductive technology, cytoplasm transfer, heteroplasmy, mitochondria, ooplasm transfer, ovary

³Correspondence: A. Jurisicova, 600 University Avenue, Samuel Lunenfeld Research Institute, Room 876, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. FAX: 416 586 8588; e-mail: jurisicova{at}mshri.on.ca

⁴Current address: SUNY Canton, Department of Health, Science and Professional Studies, Canton, NY 13617.

¹Supported by Canadian Institute of Health Research (operating grant MOP14048). B.M.A. was supported by a Canadian Institute of Health Research Doctoral Research Award, and A.J. was supported by a Canadian Institute of Health Research New Investigator Award.

Correspondence: ²R.F. Casper, 600 University Ave., Samuel Lunenfeld Research Institute, Room 876, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. FAX: 416 586 8588; e-mail: rfcasper{at}aol.com

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