Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics

DOI Web Site 84 References
  • Tasneem Qaqorh
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Yusuke Takahashi
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Kohei Sameshima
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Kentaro Otani
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Issei Yazawa
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Yuya Nishida
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Kohei Tonai
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Yoshitaka Fujihara
    Department of Advanced Medical Technologies, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Mizuki Honda
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Shinya Oki
    Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Yasuyuki Ohkawa
    Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • David R. Thorburn
    Murdoch Children’s Research Institute, Royal Children’s Hospital, and University of Melbourne, Department of Paediatrics, Parkville, Victoria, Australia.
  • Ann E. Frazier
    Murdoch Children’s Research Institute, Royal Children’s Hospital, and University of Melbourne, Department of Paediatrics, Parkville, Victoria, Australia.
  • Atsuhito Takeda
    Department of Pediatrics, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
  • Yoshihiko Ikeda
    Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Heima Sakaguchi
    Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Takuya Watanabe
    Department of Transplant Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Norihide Fukushima
    Department of Transplant Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Yasumasa Tsukamoto
    Department of Transplant Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Naomasa Makita
    Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Osamu Yamaguchi
    Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  • Kei Murayama
    Department of Metabolism, Chiba Children’s Hospital, Chiba, Japan.
  • Akira Ohtake
    Department of Pediatrics and Clinical Genomics, Saitama Medical University, Moroyama, Saitama, Japan.
  • Yasushi Okazaki
    Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
  • Takanari Kimura
    Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  • Hisakazu Kato
    Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  • Hijiri Inoue
    Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  • Ken Matsuoka
    Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  • Seiji Takashima
    Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  • Yasunori Shintani
    Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Bibliographic Information

Published
2025-04-04
Resource Type
journal article
DOI
  • 10.1126/sciadv.adq1575
Publisher
American Association for the Advancement of Science (AAAS)

Description

<jats:p> Oxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, <jats:italic>ATF3</jats:italic> . Genetic ablation of <jats:italic>Atf3</jats:italic> in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of <jats:italic>ATF3</jats:italic> in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression. </jats:p>

Journal

  • Science Advances

    Science Advances 11 (14), 2025-04-04

    American Association for the Advancement of Science (AAAS)

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