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These findings were supported by pharmacologically manipulated models in non-neuronal ACh systems and by gain- or loss-of-function models in the NNCCS. Nevertheless, the mechanisms underlying this phenomenon (i.e., sustention and protection) and the target of the NNCCS in cardiomyocytes remain to be fully elucidated. Our conditional murine model with heart-specific deletion of the choline acetyltransferase (ChAT) gene in the heart (hChAT KO mice) revealed cardiac dysfunction associated with heart failure symptoms. The representative culprit targets were the mitochondria with a disorganized appearance and dysfunction, accompanied by a reduction in mitochondrial DNA, membrane potential, and ATP production. Alternatively, malfunctioning mitochondria impaired cardiac energy metabolism and nicotinic receptor-mediated calcium responses in the mitochondria and down-regulated the mitochondrial calcium uniporter (MCU), leading to poor calcium handling by the mitochondria. The impaired cardiac function in hChAT KO mice induced systemic inflammatory responses and attenuated blood\u2013brain barrier function, further influencing higher brain functions, including the aggravation of depression-like phenomenon. These specifically characteristic phenotypes indicate that the NNCCS principally plays a crucial role in sustaining mitochondrial functions through nicotinic receptors in the mitochondria and that the signal is indispensable for maintaining mitochondrial functions and integrity.<\/jats:p>","DOI":"10.1042\/cs20257026","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:39:04Z","timestamp":1762349944000},"page":"1543-1570","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impaired cardiac non-neuronal acetylcholine synthesis triggers mitochondrial dysfunction with the loss of nicotinic receptor-mediated calcium handling, causing the failing heart"],"prefix":"10.1042","volume":"139","author":[{"given":"Takashi","family":"Sonobe","sequence":"first","affiliation":[{"name":"1Department of Bioregulatory Science, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Kai","sequence":"additional","affiliation":[{"name":"1Department of Bioregulatory Science, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shino","family":"Oikawa","sequence":"additional","affiliation":[{"name":"1Department of Bioregulatory Science, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Akagi","sequence":"additional","affiliation":[{"name":"2Department of Physiology, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asuka","family":"Mano","sequence":"additional","affiliation":[{"name":"1Department of Bioregulatory Science, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimpei","family":"Morita","sequence":"additional","affiliation":[{"name":"3Department of Microbiology and Immunology, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Tsuda","sequence":"additional","affiliation":[{"name":"4Institute for Laboratory Animal Research, Kochi Medical School, Nankoku, Kochi, 783-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5470-9128","authenticated-orcid":false,"given":"Yoshihiko","family":"Kakinuma","sequence":"additional","affiliation":[{"name":"1Department of Bioregulatory Science, Nippon Medical School, 113-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"2025112715022932800_CS-2025-7026C1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1046\/j.1440-1681.1999.03016.x","article-title":"The cholinergic \u201cpitfall\u201d: acetylcholine, a universal cell molecule in biological systems, including humans","volume":"26","author":"Wessler","year":"1999","journal-title":"Clin. 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