{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:00:52Z","timestamp":1790593252872,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020026","name":"Citrin Foundation","doi-asserted-by":"publisher","award":["RG24003"],"award-info":[{"award-number":["RG24003"]}],"id":[{"id":"10.13039\/501100020026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030_207965"],"award-info":[{"award-number":["320030_207965"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["CRSII\u2010222794"],"award-info":[{"award-number":["CRSII\u2010222794"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    ATP synthase defects, including TMEM70 and MT\u2010ATP6 deficiencies, cause severe mitochondrial encephalo\u2010(cardio)\u2010myopathies complicated by acute metabolic decompensations (AMDs) often associated with hyperammonaemia. However, detailed biochemical characterisation of these events remains limited. The aim of the study was to evaluate the metabolic profiles associated with TMEM70 and MT\u2010ATP6 deficiencies during AMDs in comparison to stable metabolic conditions, assessing frequency and severity of hyperammonaemia, and exploring the mechanisms linking impaired mitochondrial ATP production to the urea cycle by in\u00a0vivo ureagenesis studies, using [\n                    <jats:sup>15<\/jats:sup>\n                    N] ammonium chloride as stable isotope and assessed by high\u2010resolution mass\u2010spectrometry coupled with liquid chromatography. We retrospectively analysed clinical and biochemical profiles from two genetically confirmed cohorts. Patients with TMEM70 deficiency experienced more frequent AMDs, often with hyperammonaemia and requiring extracorporeal detoxification, while the MT\u2010ATP6 cohort had more prominent neurological symptoms and a lower incidence of hyperammonaemia. Biochemically, both groups showed elevated lactate, alanine and glutamine, with orotic aciduria and abnormalities in purine\/pyrimidine metabolism. Plasma citrulline levels were divergent in the two cohorts, with a consistent reduction in patients with MT\u2010ATP6 deficiency and normal or borderline elevated levels in the TMEM70 cohort. In\u00a0vivo stable isotope studies pointed to the differential impact of TMEM70 and MT\u2010ATP6 deficiency on ureagenesis and on the enrichment of individual urea cycle\u2010related amino acids. This study reveals that TMEM70 and MT\u2010ATP6 deficiencies share features of mitochondrial dysfunction but present distinct metabolic profiles, highlighting a different impact on the urea cycle and its related metabolites, and providing novel insights on our understanding of mitochondrial pathophysiology.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70244","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:45:17Z","timestamp":1789087517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Urea Cycle Dysfunction Profiles Differentiate Acute Metabolic Decompensation in\n                    <scp>TMEM70<\/scp>\n                    and\n                    <scp>MT<\/scp>\n                    \u2010\n                    <scp>ATP6<\/scp>\n                    \u2010Related Mitochondrial\n                    <scp>ATP<\/scp>\n                    Synthase Defects"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2876-4745","authenticated-orcid":false,"given":"Barbara","family":"Siri","sequence":"first","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-2871","authenticated-orcid":false,"given":"Diego","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-4054","authenticated-orcid":false,"given":"Rosalba","family":"Carrozzo","sequence":"additional","affiliation":[{"name":"Translational Cytogenomics Research Unit, Laboratory of Medical Genetics Bambino Ges\u00f9 Children's Hospital, IRCCS  Rome 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