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Tfam knockdown results in reduction of mtDNA copy number, OXPHOS deficiency and abnormalities in zebrafish embryos

Auke BC Otten, Rick Kamps, Patrick Lindsey, Mike Gerards, Hélène Pendeville-Samain, Marc Muller, Florence HJ van Tienen, View ORCID ProfileHubert JM Smeets
doi: https://doi.org/10.1101/843318
Auke BC Otten
1Department of Genetics and Cell Biology, Maastricht University, Maastricht, the Netherlands
2Department of Dermatology, University of California San Diego (UCSD), La Jolla, USA
3School for Oncology & Developmental Biology (GROW) in Maastricht University Medical Centre, Maastricht, the Netherlands
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Rick Kamps
1Department of Genetics and Cell Biology, Maastricht University, Maastricht, the Netherlands
4School for Mental Health and Neurosciences (MHeNS), Maastricht University Medical Centre, Maastricht, the Netherlands
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Patrick Lindsey
1Department of Genetics and Cell Biology, Maastricht University, Maastricht, the Netherlands
3School for Oncology & Developmental Biology (GROW) in Maastricht University Medical Centre, Maastricht, the Netherlands
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Mike Gerards
5Maastricht Centre for Systems Biology (MaCSBio), Maastricht University Medical Centre, Maastricht, the Netherlands
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Hélène Pendeville-Samain
7Laboratory of Organogenesis and Regeneration, Univérsité Liège, Liège, Belgium
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Marc Muller
7Laboratory of Organogenesis and Regeneration, Univérsité Liège, Liège, Belgium
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Florence HJ van Tienen
3School for Oncology & Developmental Biology (GROW) in Maastricht University Medical Centre, Maastricht, the Netherlands
4School for Mental Health and Neurosciences (MHeNS), Maastricht University Medical Centre, Maastricht, the Netherlands
6Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands
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Hubert JM Smeets
1Department of Genetics and Cell Biology, Maastricht University, Maastricht, the Netherlands
3School for Oncology & Developmental Biology (GROW) in Maastricht University Medical Centre, Maastricht, the Netherlands
4School for Mental Health and Neurosciences (MHeNS), Maastricht University Medical Centre, Maastricht, the Netherlands
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  • ORCID record for Hubert JM Smeets
  • For correspondence: bert.smeets@maastrichtuniversity.nl
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ABSTRACT

High mitochondrial DNA (mtDNA) copy numbers are essential for oogenesis and embryogenesis and correlate with fertility of oocytes and viability of embryos. To understand the pathology and mechanisms associated with low mtDNA copy numbers, we knocked down mitochondrial transcription factor A (Tfam), a regulator of mtDNA replication, during early zebrafish development. Reduction of Tfam using a splice-modifying morpholino (MO) resulted in a 42%±4% decrease in mtDNA copy number in embryos at 4 days post fertilization. Morphant embryos displayed abnormal development of the eye, brain, heart and muscle, as well as a 50%±11% decrease in ATP production. Transcriptome analysis revealed a decrease in protein-encoding transcripts from the heavy strand of the mtDNA. In addition, various RNA translation pathways were increased, indicating an upregulation of nuclear and mitochondria-related translation. The developmental defects observed were supported by a decreased expression of pathways related to eye development and haematopoiesis. The increase in mRNA translation might serve as a compensation mechanism, but appears insufficient during prolonged periods of mtDNA depletion, highlighting the importance of high mtDNA copy numbers for early development in zebrafish.

SUMMARY STATEMENT The first tuneable zebrafish model used to characterize the effect of a reduced mtDNA copy number and resulting OXPHOS deficiency on zebrafish embryonic development.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 14, 2019.
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Tfam knockdown results in reduction of mtDNA copy number, OXPHOS deficiency and abnormalities in zebrafish embryos
Auke BC Otten, Rick Kamps, Patrick Lindsey, Mike Gerards, Hélène Pendeville-Samain, Marc Muller, Florence HJ van Tienen, Hubert JM Smeets
bioRxiv 843318; doi: https://doi.org/10.1101/843318
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Tfam knockdown results in reduction of mtDNA copy number, OXPHOS deficiency and abnormalities in zebrafish embryos
Auke BC Otten, Rick Kamps, Patrick Lindsey, Mike Gerards, Hélène Pendeville-Samain, Marc Muller, Florence HJ van Tienen, Hubert JM Smeets
bioRxiv 843318; doi: https://doi.org/10.1101/843318

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