{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T01:06:57Z","timestamp":1788052017438,"version":"build-2784847793"},"reference-count":72,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Research Fund for the Doctoral Program of Anhui Medical University","award":["0801059201"],"award-info":[{"award-number":["0801059201"]}]},{"name":"the Research Fund for the Doctoral Program of Anhui Medical University","award":["82303057"],"award-info":[{"award-number":["82303057"]}]},{"name":"the Research Fund for the Doctoral Program of Anhui Medical University","award":["2023AFB521"],"award-info":[{"award-number":["2023AFB521"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["0801059201"],"award-info":[{"award-number":["0801059201"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82303057"],"award-info":[{"award-number":["82303057"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023AFB521"],"award-info":[{"award-number":["2023AFB521"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Hubei Province of China","award":["0801059201"],"award-info":[{"award-number":["0801059201"]}]},{"name":"Natural Science Foundation of Hubei Province of China","award":["82303057"],"award-info":[{"award-number":["82303057"]}]},{"name":"Natural Science Foundation of Hubei Province of China","award":["2023AFB521"],"award-info":[{"award-number":["2023AFB521"]}]},{"name":"\u201cChutian Scholars Program\u201d of Hubei Province of China","award":["0801059201"],"award-info":[{"award-number":["0801059201"]}]},{"name":"\u201cChutian Scholars Program\u201d of Hubei Province of China","award":["82303057"],"award-info":[{"award-number":["82303057"]}]},{"name":"\u201cChutian Scholars Program\u201d of Hubei Province of China","award":["2023AFB521"],"award-info":[{"award-number":["2023AFB521"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Mitochondrial dysfunction is implicated across a spectrum of neurological diseases, yet its causal role and mechanistic specificity remain unclear. This study employed a multi-modal integrative analysis of mitochondrial gene expression in Alzheimer\u2019s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson\u2019s Disease (PD) to address these gaps. We combined machine learning for predictive modeling with genetic causal inference methods (Mendelian Randomization, colocalization, PheWAS), followed by drug enrichment analysis and molecular docking. Our machine learning models, particularly Support Vector Machine and Multi-layer Perceptron, effectively classified these conditions, with MS exhibiting the highest predictability (mean Accuracy: 0.758). Causal inference analyses identified specific gene\u2013disease links; for instance, genetically predicted increased expression of PDK1 was causally associated with an elevated risk for both AD (OR = 1.041) and ALS (OR = 1.037), identifying pyruvate metabolism as a shared vulnerability. In contrast, genes like SLC25A38 emerged as highly predictive specifically for PD. We also observed evidence of potential brain\u2013periphery interaction, such as a bidirectional causal relationship between red blood cell indices and MS risk. Finally, drug enrichment analysis highlighted Celecoxib, and subsequent molecular docking predicted a strong binding affinity to PDK1 (docking score S = \u22126.522 kcal\/mol), generating hypotheses for potential metabolic modulation. Taken together, this study provides a computational hypothesis framework suggesting mitochondrial pathways and targets that warrant future biological validation. This study provides specific, genetically supported evidence for the causal role of mitochondrial pathways in neurological diseases and identifies tangible targets for future therapeutic development.<\/jats:p>","DOI":"10.3390\/cimb47080636","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T15:30:52Z","timestamp":1754667052000},"page":"636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Convergent and Divergent Mitochondrial Pathways as Causal Drivers and Therapeutic Targets in Neurological Disorders"],"prefix":"10.3390","volume":"47","author":[{"given":"Yanan","family":"Du","sequence":"first","affiliation":[{"name":"School of Life Sciences, Anhui Medical University, Hefei 230032, China"},{"name":"School of Health Management, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha-Sha","family":"Fan","sequence":"additional","affiliation":[{"name":"Health Science Center, Medical School, Hubei Minzu University, Enshi 445000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwen","family":"He","sequence":"additional","affiliation":[{"name":"College of Informatics, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"He","sequence":"additional","affiliation":[{"name":"College of Informatics, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5669-3502","authenticated-orcid":false,"given":"Xiang-Yu","family":"Meng","sequence":"additional","affiliation":[{"name":"Health Science Center, Medical School, Hubei Minzu University, Enshi 445000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6525-7735","authenticated-orcid":false,"given":"Xuan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/alz.12683","article-title":"The Role of Mitochondrial Dysfunction in Alzheimer\u2019s Disease Pathogenesis","volume":"19","author":"Ashleigh","year":"2023","journal-title":"Alzheimers Dement. 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