Novel Bioassay For Mitochondria Resistance To Cellular Stress: Clinical Applications

Tech ID: 27137 / UC Case 2016-071-0

Summary

Researchers at UCLA have developed a sensitive and specific assay that measures a cell’s mitochondrial resistance to stress and could increase the success rate of in vitro fertilization procedures.

Background

Despite the fact that in vitro fertilization (IVF) has resulted in the birth of over three million infants, over 50% of transferred embryos do not come to term. In light of the increasing average maternal age, it is crucial to develop technologies that improve embryo selection and the success rate of IVF. Mitochondrial resistance to stress plays a role in the success of embryo implantation and maturation, as cumulus cells, which coordinate follicular development and oocyte maturation, rely heavily on mitochondrial ATP production. In these cumulus cells that surround the ovarian follicle, inability to withstand mitochondrial stress could result in programmed cell death (apoptosis), decreased support of the embryo, and subsequent loss of the embryo. A sensitive and selective assay that measures mitochondrial resistance in cumulus cells, as a surrogate for embryo viability, could increase the success rate of IVF procedures.

Mitochondrial dysfunction is also an underlying component of many diseases, often resulting in neurological disorders. MtDNA mutations can cause Kearns-Sayre syndrome, MELAS syndrome, MERRF, and Leber’s hereditary optic neuropathy. Mitochondrial dysfunction is also linked to diabetes, autism, myopathy, Parkinson’s disease, and Alzheimer’s disease. Additionally, many cancers can cause structural and functional alterations in mitochondria to promote tumor growth and development. That malignant transformation is a potential target for therapeutics.

Current techniques use fluorescent imaging by confocal microscopy or flow cytometry to detect changes in the mitochondrial membrane potential. However, these techniques can be expensive, time-consuming, and require a large number of cells to obtain reliable data.

Innovation

The Chazenbalk group at UCLA has developed a bioassay that can specifically and sensitively detect changes in mitochondrial membrane potential. Their novel assay requires only about 100 cells and approximately two minutes to image per sample. A dye is added that specifically enters mitochondria and changes color based on the membrane potential of the organelles. In combination with this dye, chemical inhibitors can be added to measure mitochondrial resistance to stress in a specific and sensitive assay.

Applications

Improved selection of embryos during IVF resulting in increased success rate

Screening for anti-aging and anti-cancer compounds in drug discovery

Model for diseases caused by or involving mitochondrial dysfunction

  • Diabetes
  • Autism
  • Myopathy
  • Kearns-Sayre syndrome
  • MELAS syndrome
  • Leber’s hereditary optic neuropathy
  • Friedreich’s ataxia
  • Hereditary spastic paraplegia
  • Wilson’s disease
  • Barth syndrome

Advantages

  • Increases sensitivity and specificity compared to commercially available mitochondrial dyes and detection techniques
  • Quantitatively measures mitochondrial resistance to an oxidative inhibitor
  • Reduces cost of IVF by decreasing the number of procedures required
  • Reduces number of multiple-infant births, resulting from low IVF success rate, that could pose a threat to both the mother and the newborns

State Of Development

Proof of concept for this novel bioassay has been shown in cumulus cells extracted from the cumulus cell-oocyte complex of developing embryos. The inventors have also shown, in a trial of 25 patients, that mitochondrial resistance to their oxidative phosphorylation inhibitor in cumulus cells is highly correlated with oocyte viability.

Related Materials

Patent Status

Patent Pending

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Inventors

  • Chazenbalk, Gregorio D.

Other Information

Keywords

In vitro fertilization, mitochondrial stress, mitochondrial dysfunction, oxidative stress, mitochondrial resistance, drug screening

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