Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics
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, <i>ATF3</i>. Genetic ablation of <i>Atf3</i> in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of <i>ATF3</i> in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.
Authors
- Yusuke Takahashi (ORCID: https://orcid.org/0000-0002-6272-5758)
- Heima Sakaguchi (ORCID: https://orcid.org/0000-0002-7758-840X)
- Mizuki Honda (ORCID: https://orcid.org/0000-0003-3988-0802)
- Akira Ohtake (ORCID: https://orcid.org/0000-0003-1147-3113)
- Osamu Yamaguchi (ORCID: https://orcid.org/0000-0002-7461-369X)
- Tasneem Qaqorh (ORCID: https://orcid.org/0000-0002-3506-5870)
- Yasumasa Tsukamoto (ORCID: https://orcid.org/0000-0002-0963-6940)
- Shinya Oki (ORCID: https://orcid.org/0000-0002-4767-3259)
- David R. Thorburn (ORCID: https://orcid.org/0000-0002-7725-9470)
- Yuya Nishida (ORCID: https://orcid.org/0000-0002-1994-0807)
- Atsuhito Takeda (ORCID: https://orcid.org/0000-0001-9913-5834)
- Issei Yazawa
- Kentaro Otani (ORCID: https://orcid.org/0000-0001-7607-8056)
- Yoshihiko Ikeda (ORCID: https://orcid.org/0000-0001-6395-5072)
- Yasuyuki Ohkawa (ORCID: https://orcid.org/0000-0001-6440-9954)
- Hisakazu Kato (ORCID: https://orcid.org/0000-0003-4619-3680)
- Yoshitaka Fujihara (ORCID: https://orcid.org/0000-0001-8332-3507)
- Takanari Kimura
- Yasushi Okazaki (ORCID: https://orcid.org/0000-0003-3241-5502)
- Yasunori Shintani (ORCID: https://orcid.org/0000-0001-9579-0727)
- Kohei Sameshima (ORCID: https://orcid.org/0009-0006-4620-5214)
- Norihide Fukushima (ORCID: https://orcid.org/0000-0003-1367-4066)
- Ann E. Frazier (ORCID: https://orcid.org/0000-0002-6491-3437)
- Kei Murayama (ORCID: https://orcid.org/0000-0002-3923-8636)
- Ken Matsuoka (ORCID: https://orcid.org/0000-0001-7229-7294)
- Naomasa Makita (ORCID: https://orcid.org/0000-0002-1807-672X)
- Kohei Tonai (ORCID: https://orcid.org/0000-0003-3410-859X)
- Hijiri Inoue
- Takuya Watanabe (ORCID: https://orcid.org/0000-0002-9166-1749)
- Seiji Takashima (ORCID: https://orcid.org/0000-0003-1625-493X)
Institutions
- Royal Children's Hospital (AU)
- Kyushu University (JP)
- Senri Kinran University (JP)
- Hokkaido University (JP)
- Kyoto University (JP)
- Juntendo University (JP)
- Victorian Clinical Genetics Services (AU)
- National Cerebral and Cardiovascular Center (JP)
- Keiyukai Sapporo Hospital (JP)
- Chiba Hospital (JP)
- Murdoch Children's Research Institute (AU)
- Toujinkai Hospital (JP)
- Saitama Medical University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1126/sciadv.adq1575
- Citations
- 3
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.42