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SQSTM1 and its MAP1LC3B-binding domain induce forced mitophagy to degrade mitochondrial carryover during

Xiao-Yan Fan1, Shen Yin2, Shi-Ming Luo1

  • 1Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.

Autophagy
|May 16, 2022
PubMed

Insights

Forced mitophagy, a novel method, efficiently removes excess mitochondria and their DNA without harming cells. This technique significantly reduces mitochondrial carryover in mitochondrial replacement therapy (MRT), ensuring safety and efficacy.

Area of Science:

  • Cell Biology
  • Genetics
  • Reproductive Medicine

Background:

  • Mitophagy is a crucial cellular process for degrading damaged mitochondria.
  • Mitochondrial carryover in assisted reproductive technologies like MRT can lead to genetic abnormalities.
  • Existing mitophagy methods lack specificity or efficiency for therapeutic applications.

Purpose of the Study:

  • To investigate the efficacy and safety of a novel 'forced mitophagy' approach.
  • To determine if forced mitophagy can effectively reduce mitochondrial carryover in MRT.
  • To assess the impact of forced mitophagy on embryo development and offspring health.

Main Methods:

  • Ectopic expression of SQSTM1 and its MAP1LC3B-binding domain (Binding) on the mitochondrial outer membrane to induce mitophagy.
  • Application of forced mitophagy in HeLa cells, mouse embryos, and human tri-pronuclear embryos undergoing MRT.
  • Assessment of mitochondrial DNA levels, mitochondrial membrane potential, ROS, cell division, and embryo development.
  • Evaluation of offspring growth, reproduction, exercise, and behavior in mice.

Main Results:

  • Forced mitophagy effectively degraded up to 50% of mitochondria and mitochondrial DNA in cells and embryos without adverse effects.
  • Mitochondrial carryover in mouse embryos after MRT was reduced from 4% to 0.09% using forced mitophagy.
  • Undetectable mitochondrial carryover was achieved in 77% of human embryos following MRT with forced mitophagy.
  • Offspring from MRT mice exhibited normal growth, reproduction, and behavior.

Conclusions:

  • Forced mitophagy is a highly efficient and specific method for eliminating excess mitochondria.
  • This technique offers a safe and effective solution for reducing mitochondrial carryover in MRT.
  • Forced mitophagy holds significant promise for improving the safety and success rates of mitochondrial replacement therapy.
Keywords:
Forced mitophagyNIXSQSTM1mitochondrial carryovermitochondrial replacement therapy

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