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Critical role of UQCRC1 in embryo survival, brain ischemic tolerance and normal cognition in mice

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Abstract

Ubiquinol cytochrome c reductase core protein I (UQCRC1) is a component of the complex III in the respiratory chain. Its biological functions are unknown. Here, we showed that knockout of UQCRC1 led to embryonic lethality. Disrupting one UQCRC1 allele in mice (heterozygous mice) of both sexes did not affect their growth but reduced UQCRC1 mRNA and protein in the brain. These mice had decreased complex III formation, complex III activity and ATP content in the brain at baseline. They developed worsened neurological outcome after brain ischemia/hypoxia or focal brain ischemia compared with wild-type mice. The ischemic cerebral cortex of the heterozygous mice had decreased mitochondrial membrane potential and ATP content as well as increased free radicals. Also, the heterozygous mice performed poorly in the Barnes maze and novel object recognition tests. Finally, UQCRC1 was expressed abundantly in neurons and astrocytes. These results suggest a critical role of UQCRC1 in embryo survival. UQCRC1 may also be important by forming the complex III to maintain normal brain ischemic tolerance, learning and memory.

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Abbreviations

UQCRC1:

Ubiquinol cytochrome c reductase core protein I

UQCRC2:

Ubiquinol cytochrome c reductase core protein 2

MAP-2:

Microtubule associated protein 2

GFAP:

Glial fibrillary acidic protein

Iba-1:

Ionized calcium-binding adaptor molecule 1

TMEM119:

Transmembrane protein 119

MCAO:

Middle cerebral arterial occlusion

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

TTC:

2,3,5-Triphenyltetrazolium chloride

ROS:

Reactive oxygen species

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Acknowledgements

This study was supported by Grants (GM098308, AG056995, HD089999 and NS099118) from the National Institutes of General Medical Sciences and National Institutes of Health, Bethesda, MD, the Robert M. Epstein Professorship endowment, University of Virginia, Charlottesville, VA.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, PO Box 800710, Charlottesville, VA, 22908-0710, USA

    Weiran Shan, Jun Li & Zhiyi Zuo

  2. Department of Neuroscience and Neurological Surgery, University of Virginia, Charlottesville, VA, USA

    Zhiyi Zuo

  3. Genetically Engineered Murine Model Core, School of Medicine, University of Virginia, Charlottesville, VA, USA

    Wenhao Xu

  4. Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China

    Hong Li

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  1. Weiran Shan
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  2. Jun Li
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  3. Wenhao Xu
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  4. Hong Li
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  5. Zhiyi Zuo
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Contributions

ZZ conceived the project. WS, JL, WX, HL and ZZ designed the study, WS, JL and WX performed the experiments. WS did the initial data analysis and drafted Methods section. ZZ performed the final data analysis and wrote the manuscript.

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Correspondence to Zhiyi Zuo.

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Shan, W., Li, J., Xu, W. et al. Critical role of UQCRC1 in embryo survival, brain ischemic tolerance and normal cognition in mice. Cell. Mol. Life Sci. 76, 1381–1396 (2019). https://doi.org/10.1007/s00018-019-03007-6

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