{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:19:56Z","timestamp":1792516796247,"version":"4.5.0"},"posted":{"date-parts":[[2025,6,25]]},"group-title":"Neuroscience","reference-count":108,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,3]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Mitochondria supply the energy required for brain function, but how energetic capacity constrains human brain activity remains unclear. We used genetically defined mitochondrial disease as a human model of impaired bioenergetics to test whether energetic limitations produce global disruption of brain function or selective vulnerability across certain functional domains. Participants completed resting-state fMRI and tasks probing working memory, sensory perception, and affective responses to cold pain, together with behavioral, clinical, and circulating biomarker assessments. We report impairment in working memory performance and reduced activation of associated brain networks in a subset of patients with the largest clinical and cognitive impairments. A resilient subgroup showed higher working-memory\u2013related BOLD responses, which were associated with preserved task performance. Neural and behavioral effects scaled with the circulating marker of energetic stress growth differentiation factor 15 (GDF15). Brain activity related to sensory and affective responses and resting-state connectivity were comparable for patients and controls. These findings are consistent with an energy-hierarchy model and link clinical disease severity to working-memory brain responses and performance, while suggesting relative preservation of sensory and pain-related brain processes under energetic stress.<\/jats:p>","DOI":"10.1101\/2025.06.25.661482","type":"posted-content","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T14:55:11Z","timestamp":1750863311000},"source":"Crossref","is-referenced-by-count":3,"title":["Mitochondrial Energy Transformation Capacity Influences Brain Activation During Sensory, Affective, and Cognitive Tasks"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3286-7891","authenticated-orcid":false,"given":"Ke","family":"Bo","sequence":"first","affiliation":[{"name":"Department of Psychology, The University of Texas at Dallas, Richardson, TX"},{"name":"Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Trumpff","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Hirano","sequence":"additional","affiliation":[{"name":"Department of Neurology, H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia University Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0329-1814","authenticated-orcid":false,"given":"Michel","family":"Thiebaut de Schotten","sequence":"additional","affiliation":[{"name":"Groupe d\u2019Imagerie Neurofonctionnelle, Institut des Maladies Neurod\u00e9g\u00e9n\u00e9ratives-UMR 5293, CNRS, CEA, University of Bordeaux, Bordeaux, France"},{"name":"Brain Connectivity and Behaviour Laboratory, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Picard","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, USA"},{"name":"Department of Neurology, H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia University Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, USA"},{"name":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tor D.","family":"Wager","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100707551398000_2025.06.25.661482v6.1","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-200110000-00001"},{"key":"2026100707551398000_2025.06.25.661482v6.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172399499"},{"key":"2026100707551398000_2025.06.25.661482v6.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2022.102668"},{"key":"2026100707551398000_2025.06.25.661482v6.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2010.01.008"},{"key":"2026100707551398000_2025.06.25.661482v6.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.316"},{"key":"2026100707551398000_2025.06.25.661482v6.6","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00062.2017"},{"key":"2026100707551398000_2025.06.25.661482v6.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1913042117"},{"key":"2026100707551398000_2025.06.25.661482v6.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-22048-9"},{"key":"2026100707551398000_2025.06.25.661482v6.9","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2016.180"},{"key":"2026100707551398000_2025.06.25.661482v6.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-00993-z"},{"key":"2026100707551398000_2025.06.25.661482v6.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-024-02725-z"},{"key":"2026100707551398000_2025.06.25.661482v6.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.03.025"},{"key":"2026100707551398000_2025.06.25.661482v6.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2016.05.018"},{"key":"2026100707551398000_2025.06.25.661482v6.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2017.03.009"},{"key":"2026100707551398000_2025.06.25.661482v6.15","first-page":"239","article-title":"Metabolism matters in mental health","volume":"10","year":"2025","journal-title":"Biol. 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