{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T08:13:46Z","timestamp":1770884026478,"version":"3.50.1"},"reference-count":120,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Hypermobile Ehlers\u2013Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and systemic manifestations such as chronic fatigue, gastrointestinal dysfunction, and neurological symptoms. Unlike other EDS subtypes with known genetic mutations, hEDS lacks definitive markers, suggesting a multifactorial etiology involving both mitochondrial dysfunction and non-mitochondrial pathways. This scoping review, conducted in accordance with the PRISMA-ScR guidelines, highlights mitochondrial dysfunction as a potential unifying mechanism in hEDS pathophysiology. Impaired oxidative phosphorylation (OXPHOS), elevated reactive oxygen species (ROS) levels, and calcium dysregulation disrupt cellular energetics and extracellular matrix (ECM) homeostasis, contributing to the hallmark features of hEDS. We reviewed candidate genes associated with ECM remodeling, signaling pathways, and immune regulation. Protein\u2013protein interaction (PPI) network analyses revealed interconnected pathways linking mitochondrial dysfunction with these candidate genes. Comparative insights from Fabry disease and fragile X premutation carriers underscore shared mechanisms such as RNA toxicity, matrix metalloproteinases (MMP) activation, and ECM degradation. These findings may suggest that mitochondrial dysfunction amplifies systemic manifestations through its interplay with non-mitochondrial molecular pathways. By integrating these perspectives, this review provides a potential framework for understanding hEDS pathogenesis while highlighting latent avenues for future research into its molecular basis. Understanding the potential role of mitochondrial dysfunction in hEDS not only sheds light on its complex molecular etiology but also opens new paths for targeted interventions.<\/jats:p>","DOI":"10.3390\/cimb47020134","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T03:29:53Z","timestamp":1739935793000},"page":"134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mitochondrial Dysfunction and Its Potential Molecular Interplay in Hypermobile Ehlers\u2013Danlos Syndrome: A Scoping Review Bridging Cellular Energetics and Genetic Pathways"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5286-2576","authenticated-orcid":false,"given":"Purusha","family":"Shirvani","sequence":"first","affiliation":[{"name":"Ehlers-Danlos Syndrome Clinical Research Program, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2847-4737","authenticated-orcid":false,"given":"Arash","family":"Shirvani","sequence":"additional","affiliation":[{"name":"Ehlers-Danlos Syndrome Clinical Research Program, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6023-9062","authenticated-orcid":false,"given":"Michael","family":"Holick","sequence":"additional","affiliation":[{"name":"Ehlers-Danlos Syndrome Clinical Research Program, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11613","DOI":"10.3390\/cimb46100689","article-title":"Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome","volume":"46","author":"Shirvani","year":"2024","journal-title":"Curr. 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