{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:24:08Z","timestamp":1787498648345,"version":"build-2736575974"},"reference-count":97,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["92736"],"award-info":[{"award-number":["92736"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["117424"],"award-info":[{"award-number":["117424"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Direct injury of mitochondrial respiratory chain (RC) complex I by Ndufs4 subunit mutations results in complex I deficiency (CID) and a progressive encephalomyopathy, known as Leigh syndrome. While mitochondrial, cytosolic and multi-organelle pathways are known to be involved in the neuromuscular LS pathogenesis, compartment-specific metabolomics has, to date, not been applied to murine models of CID. We thus hypothesized that sub-cellular metabolomics would be able to contribute organelle-specific insights to known Ndufs4 metabolic perturbations. To that end, whole brains and skeletal muscle from late-stage Ndufs4 mice and age\/sex-matched controls were harvested for mitochondrial and cytosolic isolation. Untargeted 1H-NMR and semi-targeted LC-MS\/MS metabolomics was applied to the resulting cell fractions, whereafter important variables (VIPs) were selected by univariate statistics. A predominant increase in multiple targeted amino acids was observed in whole-brain samples, with a more prominent effect at the mitochondrial level. Similar pathways were implicated in the muscle tissue, showing a greater depletion of core metabolites with a compartment-specific distribution, however. The altered metabolites expectedly implicate altered redox homeostasis, alternate RC fueling, one-carbon metabolism, urea cycling and dysregulated proteostasis to different degrees in the analyzed tissues. A first application of EDTA-chelated magnesium and calcium measurement by NMR also revealed tissue- and compartment-specific alterations, implicating stress response-related calcium redistribution between neural cell compartments, as well as whole-cell muscle magnesium depletion. Altogether, these results confirm the ability of compartment-specific metabolomics to capture known alterations related to Ndufs4 KO and CID while proving its worth in elucidating metabolic compartmentalization in said pathways that went undetected in the diluted whole-cell samples previously studied.<\/jats:p>","DOI":"10.3390\/metabo11100658","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T21:38:09Z","timestamp":1632865089000},"page":"658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sub-Cellular Metabolomics Contributes Mitochondria-Specific Metabolic Insights to a Mouse Model of Leigh Syndrome"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5383-439X","authenticated-orcid":false,"given":"Gunter","family":"van der Walt","sequence":"first","affiliation":[{"name":"Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8017-4278","authenticated-orcid":false,"given":"Jeremie Z.","family":"Lindeque","sequence":"additional","affiliation":[{"name":"Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayne","family":"Mason","sequence":"additional","affiliation":[{"name":"Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-8644","authenticated-orcid":false,"given":"Roan","family":"Louw","sequence":"additional","affiliation":[{"name":"Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.cell.2012.02.035","article-title":"Mitochondria: In sickness and in health","volume":"148","author":"Nunnari","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1289\/ehp.1408418","article-title":"Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress","volume":"122","author":"Shaughnessy","year":"2014","journal-title":"Environ. 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