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Sublethal endoplasmic reticulum stress caused by the mutation of immunoglobulin heavy chain-binding protein induces the synthesis of a mitochondrial protein, pyrroline-5-carboxylate reductase 1

Cell Stress and Chaperones volume 22, pages 77–85 (2017)Cite this article

Abstract

Most human neurodegenerative diseases are sporadic and appear later in life. Aging and neurodegeneration are closely associated, and recent investigations reveal that endoplasmic reticulum (ER) stress is involved in the progression of these features. Immunoglobulin heavy chain-binding protein (BiP) is an ER chaperone that is central to ER functions. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence to elucidate the effect of a functional defect in an ER chaperone in multicellular organisms. The homozygous mutant BiP mice died within several hours after birth because of respiratory failure with an impaired biosynthesis of pulmonary surfactant by alveolar type II cells. The heterozygous mutant BiP mice grew up to be apparently normal adults, although some of them revealed motor disabilities as they aged. Here, we report that the synthesis of a mitochondrial protein, pyrroline-5-carboxylate reductase 1 (PYCR1), is enhanced in the brains of homozygous mutant BiP mice. We performed a two-dimensional gel analysis followed by liquid chromatography-tandem mass spectrometry. PYCR1 was identified as one of the enhanced proteins. We also found that sublethal ER stress caused by tunicamycin treatment induced the synthesis of PYCR1 in murine fibroblasts. PYCR1 has been shown to be related to the aging process. Mutations in the PYCR1 gene cause cutis laxa with progeroid features and mental retardation. These findings suggest a pathophysiological interaction between ER stress and a mitochondrial function in aging.

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Acknowledgments

We thank Drs T. Nishino and S. Isono for the kind support. This work was supported by grants in aids for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan to TA (20059008).

Authors’ contributions

TA conceived and coordinated the study and wrote the article. HJ and TA designed, performed, and analyzed experiments. MK performed experiments. KS analyzed experiments and provided assistance for the preparation of paper. All authors reviewed the results and approved the final version of the manuscript.

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Affiliations

  1. Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan

    Hisayo Jin & Mari Komita

  2. Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan

    Hisayo Jin & Haruhiko Koseki

  3. Pain Center, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara City, Chiba, 299-0111, Japan

    Tomohiko Aoe

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  1. Hisayo Jin
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  2. Mari Komita
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  3. Haruhiko Koseki
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  4. Tomohiko Aoe
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Correspondence to Tomohiko Aoe.

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Jin, H., Komita, M., Koseki, H. et al. Sublethal endoplasmic reticulum stress caused by the mutation of immunoglobulin heavy chain-binding protein induces the synthesis of a mitochondrial protein, pyrroline-5-carboxylate reductase 1. Cell Stress and Chaperones 22, 77–85 (2017). https://doi.org/10.1007/s12192-016-0741-1

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  • DOI: https://doi.org/10.1007/s12192-016-0741-1

Keywords

  • Aging
  • Chaperone
  • ER stress
  • Mitochondria
  • UPR