[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-detail-455609-en":59,"doc-seo-455609-105":81},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":5,"data":60},{"doc_id":61,"user_id":62,"nickname":63,"user_avatar":64,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":66,"doc_content":67,"file_id":68,"file_url":69,"file_type":70,"file_size":71,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":72,"language":73,"language_code":74,"site_id":75,"html_lang":74,"table_of_contents":76,"faqs":77,"seo_title":78,"seo_description":66,"update_tm":79,"read_time":80},455609,687197207639,"Asher","https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Tau–Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential","Tau is a microtubule-associated MAPT-encoded neuronal protein whose alternative splicing produces isoforms with distinct N-terminal inserts and 3R/4R repeat domains, influencing oligomerization, aggregation propensity, and post-translational modification patterns. Beyond stabilizing microtubules, tau is increasingly linked to mitochondria, interacting across multiple mitochondrial compartments and mechanisms. Evidence described here shows tau localizes to outer membrane, intermembrane space, and matrix, impairing the electron transport chain, inhibiting ATP synthase, and reducing ATP production, while also disrupting axonal transport, mitochondrial fission/fusion, mitophagy, mitochondria–nucleus signaling, calcium buffering, and ROS control, thereby driving synaptic dysfunction, oxidative stress, and neuronal vulnerability. Mechanistic insights support tau as a therapeutic target and summarize clinical applications under testing.","Cellular and Molecular Neurobiology (2026) 46:3  \n[https://doi.org/10.1007/s10571-025-01634-1](https://doi.org/10.1007/s10571-025-01634-1)  \nREVIEW PAPER  \nTau–Mitochondria Interactions in Neurodegeneration: Mechanismsand Therapeutic Potential  \nYaisa Castillo-Casaña1 · Clorinda Arias2 · Roberto Coria1  \nReceived: 18 June 2025 / Accepted: 10 November 2025 © The Author(s) 2025  \nAbstract  \nTau is a microtubule-associated protein encoded by the MAPT gene and is mainly expressed in neurons. Alternative splicing generates preferentially six isoforms differing in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R) . Isoform expression varies by cell type, developmental stage, and neuronal maturation. Structurally, 4R isoforms bind and stabilize microtubules more effectively than 3R isoforms, while 3R variants are more prone to oligomerization. Differences among isoforms also affect aggregation and post-translational modification patterns, yet their specific roles in tauopathies remain unclear. Beyond its role in microtubule stabilization, tau is increasingly recognized for its functions in other cellular compartments, particularly mitochondria, where it may contribute to mitochondrial dysfunction in neurodegenerative diseases. Its intrinsically disordered conformation and extensive post-translational modifications enable interactions with multiple mitochondrial components, linking tau biology to broader aspects of neuronal health and pathology. The main focus of this review is to analyze how tau protein interacts with mitochondria and disrupts their function. Literature evidence indicates that tau localizes to the outer mitochondrial membrane, intermembrane space, and matrix, where it interferes with key processes. These include disruption of electron transport chain activity, inhibition of ATP synthase, and reduced ATP production, ultimately compromising neuronal energy supply. In parallel, tau destabilizes microtubule-based trafficking, impairing axonal transport and mitochondrial distribution, while also disrupting fission and fusion dynamics that shape mitochondrial morphology. Quality control pathways are affected as well, with tau altering mitophagy and mitochondria-nucleus signaling. Moreover, tau dysregulates calcium buffering and increases reactive oxygen species production, thereby promoting synaptic dysfunction, oxidative stress, and mitochondrial damage. Collectively, these facts establish tau as a central mediator of mitochondrial impairment and neuronal vulnerability. Elucidating the mechanisms by which tau affects mitochondrial physiology underscores its importance as a therapeutic target, with strategies aimed at preserving mitochondrial integrity offering promising avenues to slow neurodegenerative progression. In the last section, we include examples of clinical applications currently in various phases of testing, some of which show promising potential for implementation.  \nKeywords Tau protein · Mitochondrial dysfunctions · Mitochondrial bioenergetics · Mitochondrial transport · Mitochondrial dynamics · Mitophagy · Neurodegeneration · Tauopathies  \n􀀍 Yaisa Castillo-Casaña[ycastillo@ifc.unam.mx](ycastillo@ifc.unam.mx)  \nRoberto Coria  \n[rcoria@ifc.unam.mx](rcoria@ifc.unam.mx)  \n1 Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Cd Mex 04510, México  \n2 Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Cd Mex 04510, México  \nIntroduction  \nNeurodegenerative diseases are a group of complex disorders characterized by abnormal protein aggregation in the central or peripheral nervous system, leading to progressive neuronal death and functional decline (Gadhave et al. 2024) . The exact causes of many of them remain unclear, posing significant challenges for treatment development. Proteins such as α-synuclein, huntingti","cbCaioL9zlTv83Hm","https://ap.wps.com/l/cbCaioL9zlTv83Hm","pdf",3224173,17,"English","en",105,"# Introduction\n# Tau Structure\n# Tau–Mitochondria Localization and Mechanistic Disruption\n## Mitochondrial bioenergetics and ATP impairment\n## Mitochondrial trafficking and morphology\n## Quality control, mitophagy, and signaling\n## Calcium buffering, ROS, and oxidative damage\n# Therapeutic Potential and Clinical Applications","[{\"question\":\"How do tau isoforms differ and why does that matter for disease?\",\"answer\":\"Alternative splicing generates isoforms that vary in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R). These differences influence microtubule binding, oligomerization tendency, and patterns of aggregation and post-translational modifications, which remain incompletely defined across tauopathies.\"},{\"question\":\"What mitochondrial functions does tau disrupt according to the review?\",\"answer\":\"Tau interferes with mitochondrial bioenergetics and quality control. The review links tau to impaired electron transport chain activity, reduced ATP synthesis via ATP synthase inhibition, disrupted mitochondrial trafficking, altered fission/fusion dynamics, disturbed mitophagy, and perturbed mitochondria–nucleus signaling.\"},{\"question\":\"Why is tau considered a promising therapeutic target?\",\"answer\":\"The review frames tau as a central mediator of mitochondrial impairment and neuronal vulnerability. It argues that preserving mitochondrial integrity through interventions targeting tau-related mechanisms may slow neurodegenerative progression, and it includes examples of clinical strategies in testing phases.\"}]","Tau–Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential | PDF",1790743620,43,{"code":4,"msg":82,"data":83},"ok",{"site_id":75,"language":74,"slug":84,"title":65,"keywords":85,"description":66,"schema_data":86,"social_meta":140,"head_meta":142,"extra_data":144,"updated_unix":145},"taumitochondria-interactions-in-neurodegeneration-mechanisms-and-therapeutic-potential","",{"@graph":87,"@context":139},[88,102,122],{"@type":89,"itemListElement":90},"BreadcrumbList",[91,95,97,100],{"item":92,"name":93,"@type":94,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":96,"name":9,"@type":94,"position":14},"https://docshare.wps.com/document/",{"item":98,"name":40,"@type":94,"position":99},"https://docshare.wps.com/document/research-report/",3,{"item":101,"name":65,"@type":94,"position":19},"https://docshare.wps.com/document/taumitochondria-interactions-in-neurodegeneration-mechanisms-and-therapeutic-potential/455609/",{"url":101,"name":65,"@type":103,"image":104,"author":109,"headline":65,"publisher":111,"fileFormat":114,"inLanguage":74,"description":66,"dateModified":115,"datePublished":116,"encodingFormat":114,"isAccessibleForFree":117,"interactionStatistic":118},"DigitalDocument",{"url":105,"@type":106,"width":107,"height":108},"https://docshare.wps.com/thumbnails/taumitochondria-interactions-in-neurodegeneration-mechanisms-and-therapeutic-potential/455609.png","ImageObject",300,407,{"name":63,"@type":110},"Person",{"url":92,"name":112,"@type":113},"DocShare","Organization","application/pdf","2026-10-07","2026-09-30",true,{"@type":119,"interactionType":120,"userInteractionCount":39},"InteractionCounter",{"@type":121},"ViewAction",{"@type":123,"mainEntity":124},"FAQPage",[125,131,135],{"name":126,"@type":127,"acceptedAnswer":128},"How do tau isoforms differ and why does that matter for disease?","Question",{"text":129,"@type":130},"Alternative splicing generates isoforms that vary in N-terminal inserts (0, 1, or 2N) and microtubule-binding repeats (3R or 4R). These differences influence microtubule binding, oligomerization tendency, and patterns of aggregation and post-translational modifications, which remain incompletely defined across tauopathies.","Answer",{"name":132,"@type":127,"acceptedAnswer":133},"What mitochondrial functions does tau disrupt according to the review?",{"text":134,"@type":130},"Tau interferes with mitochondrial bioenergetics and quality control. The review links tau to impaired electron transport chain activity, reduced ATP synthesis via ATP synthase inhibition, disrupted mitochondrial trafficking, altered fission/fusion dynamics, disturbed mitophagy, and perturbed mitochondria–nucleus signaling.",{"name":136,"@type":127,"acceptedAnswer":137},"Why is tau considered a promising therapeutic target?",{"text":138,"@type":130},"The review frames tau as a central mediator of mitochondrial impairment and neuronal vulnerability. It argues that preserving mitochondrial integrity through interventions targeting tau-related mechanisms may slow neurodegenerative progression, and it includes examples of clinical strategies in testing phases.","https://schema.org",{"og:url":101,"og:type":141,"og:title":65,"og:site_name":112,"og:description":66},"article",{"robots":143,"canonical":101},"index,follow",{"doc_id":61,"site_id":75},1790794654]