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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,\n                    <jats:italic>ATF3<\/jats:italic>\n                    . Genetic ablation of\n                    <jats:italic>Atf3<\/jats:italic>\n                    in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of\n                    <jats:italic>ATF3<\/jats:italic>\n                    in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adq1575","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T13:59:14Z","timestamp":1743775154000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3506-5870","authenticated-orcid":true,"given":"Tasneem","family":"Qaqorh","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center, Suita, Osaka, 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