{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:10:11Z","timestamp":1788667811882,"version":"build-2803163510"},"reference-count":55,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100014055","name":"U.S. Army Medical Research Acquisition Activity","doi-asserted-by":"publisher","award":["W81XWH2210590"],"award-info":[{"award-number":["W81XWH2210590"]}],"id":[{"id":"10.13039\/100014055","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Florida Heart Research Institute"},{"name":"Children\u2019s Hospital of Philadelphia Research Institute"},{"name":"Stokes Investigator Fund"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Therapeutic Advances in Rare Disease"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (\n                      <jats:sc>l<\/jats:sc>\n                      -arginine or\n                      <jats:sc>l<\/jats:sc>\n                      -citrulline).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Following PRISMA 2020 guidelines, we conducted a comprehensive search (inception\u2013October 2025) identifying clinical studies of genetically or clinically confirmed mitochondrial disease with quantitative endothelial or bioenergetic endpoints. Eligible measures included flow-mediated dilation (FMD), reactive hyperemia index (RHI), passive-leg-movement (PLM) hyperemia, absolute synthesis rate of NO metabolites (ASR NOm), and positron emission tomography (PET)-derived myocardial oxidative indices (\n                      <jats:italic toggle=\"yes\">k<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic toggle=\"yes\">mono<\/jats:italic>\n                      <\/jats:sub>\n                      , DP\/\n                      <jats:italic toggle=\"yes\">k<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic toggle=\"yes\">mono<\/jats:italic>\n                      <\/jats:sub>\n                      ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle\u2013Ottawa Scale.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8\u201363 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following\n                      <jats:sc>l<\/jats:sc>\n                      -arginine or\n                      <jats:sc>l<\/jats:sc>\n                      -citrulline supplementation are consistent with a role for impaired endothelial NO signaling in the vascular manifestations of mitochondrial disease. These findings highlight the vascular endothelium as a potential therapeutic target and underscore the need for future clinical intervention trials that use standardized vascular and bioenergetic endpoints.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/26330040261480132","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T07:06:26Z","timestamp":1788505586000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial\u2013mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction"],"prefix":"10.1177","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9401-2226","authenticated-orcid":false,"given":"Jose A.","family":"Adams","sequence":"first","affiliation":[{"name":"Mount Sinai Medical Center"},{"name":"Department of Research, Semyon & Janna Friedman Advanced Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Ko","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia"},{"name":"Perelman School of Medicine, University of Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laith R.","family":"Sultan","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejas","family":"Sarna","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6006-1426","authenticated-orcid":false,"given":"Daniel","family":"McGinn","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkady","family":"Uryash","sequence":"additional","affiliation":[{"name":"Mount Sinai Medical Center"},{"name":"Department of Research, Semyon & Janna Friedman Advanced Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose R.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Research, Semyon & Janna Friedman Advanced Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay","family":"Nadkarni","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia"},{"name":"Perelman School of Medicine, University of Pennsylvania"},{"name":"University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiao","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni J.","family":"Falk","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia"},{"name":"University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Ischiropoulos","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Philadelphia, PA, USA"},{"name":"University of Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0743-8879","authenticated-orcid":false,"given":"Zarazuela","family":"Zolkipli-Cunningham","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia"},{"name":"University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-12-34"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.10.011"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.174"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-025-01162-x"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.040551"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000686"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2016.07.003"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0264-z"},{"key":"e_1_3_6_10_2","article-title":"Mitochondrial Genetics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association","volume":"153","author":"Fetterman JL","year":"2025","unstructured":"Fetterman JL, Chinnery PF, McClellan R, et al. 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