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

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

Journal Sci. Adv. 11(14):eadq1575 (2025)
Title Atf3 controls transitioning in female mitochond
Laboratory Laboratory of Medical Biochemistry〈Prof. TAKASHIMA Seiji〉
Abstract

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, ATF3. Genetic ablation of Atf3 in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of ATF3 in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.

Authors

Tasneem Qaqorh (1, 2), Yusuke Takahashi (1), Kohei Sameshima (1), Kentaro Otani (1), Issei Yazawa (1), Yuya Nishida (1), Kohei Tonai (1), Yoshitaka Fujihara (3), Mizuki Honda (4), Shinya Oki (4), Yasuyuki Ohkawa (5), David R Thorburn (6, 7), Ann E Frazier (6), Atsuhito Takeda (8), Yoshihiko Ikeda (9), Heima Sakaguchi (10), Takuya Watanabe (11), Norihide Fukushima (11, 12), Yasumasa Tsukamoto (11), Naomasa Makita (13, 14), Osamu Yamaguchi (13), Kei Murayama (15, 16), Akira Ohtake (17), Yasushi Okazaki (16), Takanari Kimura (2), Hisakazu Kato (2), Hijiri Inoue (2), Ken Matsuoka (2), Seiji Takashima (2), Yasunori Shintani (1)

  1. Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  2. Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  3. Department of Advanced Medical Technologies, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  4. Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  5. Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  6. Murdoch Children's Research Institute, Royal Children's Hospital, and University of Melbourne, Department of Paediatrics, Parkville, Victoria, Australia.
  7. Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, Victoria, Australia.
  8. Department of Pediatrics, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
  9. Department of Pathology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  10. Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  11. Department of Transplant Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  12. Senri Kinran University, Suita, Osaka, Japan.
  13. Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
  14. Department of Cardiology, Sapporo Teishinkai Hospital, Sapporo, Japan.
  15. Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
  16. Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
  17. Department of Pediatrics and Clinical Genomics, Saitama Medical University, Moroyama, Saitama, Japan.
PubMed 40184463

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