{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T04:46:13Z","timestamp":1790138773539,"version":"4.0.1"},"reference-count":113,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research"},{"name":"Department of Translational Medicine, University of Eastern Piedmont"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic\u2013pituitary\u2013adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind\u2013body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care.<\/jats:p>","DOI":"10.3390\/biom16010117","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T14:32:38Z","timestamp":1767882758000},"page":"117","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7517-2574","authenticated-orcid":false,"given":"Sakthipriyan","family":"Venkatesan","sequence":"first","affiliation":[{"name":"Laboratory of Physiology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6862-9468","authenticated-orcid":false,"given":"Cristoforo","family":"Comi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-1880","authenticated-orcid":false,"given":"Fabiola","family":"De Marchi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2583-6433","authenticated-orcid":false,"given":"Teresa","family":"Esposito","sequence":"additional","affiliation":[{"name":"Anesthesiologist Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Gramaglia","sequence":"additional","affiliation":[{"name":"Psychiatric Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3338-5416","authenticated-orcid":false,"given":"Carlo","family":"Smirne","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-4688","authenticated-orcid":false,"given":"Mohammad Mostafa","family":"Ola Pour","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-0155","authenticated-orcid":false,"given":"Mario","family":"Pirisi","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4625-4367","authenticated-orcid":false,"given":"Rosanna","family":"Vaschetto","sequence":"additional","affiliation":[{"name":"Anesthesiologist Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Zeppegno","sequence":"additional","affiliation":[{"name":"Psychiatric Unit, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3012-259X","authenticated-orcid":false,"given":"Elena","family":"Grossini","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1056\/NEJMsa013404","article-title":"Psychological Sequelae of the September 11 Terrorist Attacks in New York City","volume":"346","author":"Galea","year":"2002","journal-title":"N. 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