Abstract
Multidrug resistance transporters (MDRs) are best known for their pathological role in neoplastic evasion of chemotherapeutics and antibiotics. Here we show that MDR-1 is present in the oocyte mitochondrial membrane, and it protects the female gamete from oxidative stress. Female mdr1a mutant mice have no significant difference in ovarian follicular counts and stages, nor in reproductively functioning hormone levels, yet these mice are significantly more vulnerable to gonadotoxic chemotherapy, have chronically elevated reactive oxygen species in immature germinal vesicle oocytes, exhibit a significant over-accumulation of metabolites involved in the tricarboxylic acid cycle (TCA), and have abnormal mitochondrial membrane potential. The mdr1a mutant ovaries have a dramatically different transcriptomic profile with upregulation of genes involved in metabolism. Our findings indicate that functionality of MDR-1 reveals a critical intersection of metabolite regulation, oxidative stress, and mitochondrial dysfunction that has direct implications for human infertility, premature reproductive aging due to oxidative stress, and gonadoprotection.
Highlights
Multidrug resistance transporters (MDRs) belong to a family of ATP Binding Cassette (ABC) transporters with 49 genes in the human[1]
We observed that oocytes of mdr1a mutant mice had lower ratios of red to green fluorescence (p = 0.0089), very similar to levels detected in carbonyl cyanide 3-chlorophenylhydrazone (CCCP) treated positive controls, which is indicative of disturbed, non-negative mitochondrial membrane potential and potentially apoptosis (Fig. 4E,F)
In an effort to further study the role of Multidrug Resistance Transporter 1 (MDR-1) in oocyte mitochondrial function, we examined the localization of MDR-1 protein in wild type oocytes of fixed wild type ovaries
Summary
Multidrug resistance transporters (MDRs) belong to a family of ATP Binding Cassette (ABC) transporters with 49 genes in the human[1]. Recent work has begun to reveal a link between abnormal MDR-1 expression and decreased mitochondrial functionality[11] This link has been further fortified by the localization of MDR-1 to the mitochondrion[12] and its subsequent upregulation mitigating oxidative stress in retinal cells[13]. Our subsequent research in mdr1a/mdr1b/bcrp−/− knockout animals showed that loss of these transporters caused metabolite accumulations potentially signaling increased oxidative stress[16] This finding increased our focus on the interaction between MDR-1 and the mitochondrion in the oocyte. We have observed that the oocyte mitochondrion does express MDR-1, and that the ovary has markedly distinct functional features including increased oxidative stress, susceptibility to chemotherapeutics, and distinct gene expression and metabolic profiles
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