{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T13:19:30Z","timestamp":1770902370576,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5\u201320% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G&gt;A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development.<\/jats:p>","DOI":"10.3390\/cells15030276","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:49:44Z","timestamp":1770036584000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2879-9497","authenticated-orcid":false,"given":"Jon","family":"Ondaro","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9766-963X","authenticated-orcid":false,"given":"Jose Luis","family":"Z\u00fa\u00f1iga-Elizari","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nica","family":"Zufir\u00eda","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maddi","family":"Garciandia-Arcelus","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngela S\u00e1nchez","family":"Molleda","sequence":"additional","affiliation":[{"name":"Miaker Developments SL, Miaker Bioassays, 20014 San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miren","family":"Zulaica","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3402-1152","authenticated-orcid":false,"given":"Miguel","family":"Lafarga","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Department of Anatomy and Cell Biology, University of Cantabria, 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Riancho","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Hospital General Sierrallana-IDIVAL, 39300 Torrelavega, Spain"},{"name":"Department of Medicine and Psychiatry, University of Cantabria, 39005 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9509-4032","authenticated-orcid":false,"given":"Adolfo","family":"L\u00f3pez de Muna\u00edn","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Donostia University Hospital, 20014 San Sebastian, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5200-3164","authenticated-orcid":false,"given":"Fermin","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Biogipuzkoa Health Research Institute (IIS Biogipuzkoa), 20014 San Sebastian, Spain"},{"name":"Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Donostia University Hospital, 20014 San Sebastian, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2002-5531","authenticated-orcid":false,"given":"Francisco 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Faculty of Medicine and Nursing, University of Basque Country (UPV-EHU), 48940 Leioa, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/S0140-6736(15)00461-4","article-title":"Frontotemporal Dementia","volume":"386","author":"Bang","year":"2015","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1212\/WNL.0b013e3181bf997a","article-title":"The Heritability and Genetics of Frontotemporal Lobar Degeneration","volume":"73","author":"Rohrer","year":"2009","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrneurol.2012.117","article-title":"Advances in Understanding the Molecular Basis of Frontotemporal Dementia","volume":"8","author":"Rademakers","year":"2012","journal-title":"Nat. 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