A novel protein CYTB-187AA encoded by the mitochondrial gene CYTB modulates mammalian early development

  • Cell Metab. 2024 Apr 29:S1550-4131(24)00132-3. doi: 10.1016/j.cmet.2024.04.012.
Zhijuan Hu  1 ,  Liang Yang  2 ,  Maolei Zhang  2 ,  Haite Tang  2 ,  Yile Huang  3 ,  Yujie Su  4 ,  Yingzhe Ding  3 ,  Chong Li  2 ,  Mengfei Wang  4 ,  Yunhao Zhou  4 ,  Qing Zhang  5 ,  Liman Guo  5 ,  Yue Wu  5 ,  Qianqian Wang  6 ,  Ning Liu  6 ,  Haoran Kang  2 ,  Yi Wu  2 ,  Deyang Yao  2 ,  Yukun Li  4 ,  Zifeng Ruan  4 ,  Hao Wang  2 ,  Feixiang Bao  2 ,  Guopan Liu  3 ,  Junwei Wang  2 ,  Yaofeng Wang  3 ,  Wuming Wang  7 ,  Gang Lu  7 ,  Dajiang Qin  8 ,  Duanqing Pei  9 ,  Wai-Yee Chan  7 ,  Xingguo Liu  10
Affiliations
  • 1. Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, SAR, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China.
  • 2. Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 3. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, SAR, China.
  • 4. Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China.
  • 5. Proteomics and Metabolomics Core Facility, Guangzhou National Laboratory, Guangzhou, China.
  • 6. State Key Laboratory of Medicinal Chemistry Biology, Nankai University, Tianjin, China.
  • 7. CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, CUHK-Jinan University Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.
  • 8. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, SAR, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 9. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, SAR, China; Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China.
  • 10. Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, SAR, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, China-New Zealand Joint Laboratory on Biomedicine and Health, CUHK-GIBH Joint Research Laboratory on Stem Cells and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. Electronic address: [email protected].
PMID: 38703762 DOI: 10.1016/j.cmet.2024.04.012
Abstract

The mitochondrial genome transcribes 13 mRNAs coding for well-known proteins essential for Oxidative Phosphorylation. We demonstrate here that cytochrome b (CYTB), the only mitochondrial-DNA-encoded transcript among complex III, also encodes an unrecognized 187-amino-acid-long protein, CYTB-187AA, using the standard genetic code of cytosolic ribosomes rather than the mitochondrial genetic code. After validating the existence of this mtDNA-encoded protein arising from cytosolic translation (mPACT) using mass spectrometry and antibodies, we show that CYTB-187AA is mainly localized in the mitochondrial matrix and promotes the pluripotent state in primed-to-naive transition by interacting with solute carrier family 25 member 3 (SLC25A3) to modulate ATP production. We further generated a transgenic knockin mouse model of CYTB-187AA silencing and found that reduction of CYTB-187AA impairs females' fertility by decreasing the number of ovarian follicles. For the first time, we uncovered the novel mPACT pattern of a mitochondrial mRNA and demonstrated the physiological function of this 14th protein encoded by mtDNA.

Keywords
early development; mitochondria; mitochondrial DNA; ovarian follicles; pluripotency; primed-to-naive transition; ribosomes; translation.
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