Mitochondrial energetic failure underlies FLVCR1-related sensory neuropathy

Year: 2026

Type: article

Abstract: Genetic pain loss disorders represent a heterogeneous group of rare diseases mainly characterized by defective nociception. Understanding the underlying molecular mechanism is fundamental to improve the treatment of patients affected by these rare disorders. Feline Leukemia Virus Subgroup C Receptor 1 (FLVCR1) is one of the genes previously associated with sensory neuropathy that requires further investigation. Here, we report on two additional patients with novel disease-causing variants in FLVCR1 and introduce a zebrafish model of the disease. The analyses of patient-derived fibroblasts show that distinct FLVCR1 variants compromised all the known functions associated with FLVCR1, thus affecting choline levels, heme biosynthesis and mitochondrial Ca2+ handling. Furthermore, we provide evidence that the alteration of these processes impairs the TCA cycle and OXPHOS, and induces lipid peroxidation. Our data points to the alterations of energetic metabolism as a potential driving pathomechanism in FLVCR1-associated sensory neuropathy. Functional studies of pathogenetic FLVCR1 variants associated with sensory neuropathy reveal that impaired choline uptake, heme biosynthesis, and ER–mitochondria Ca²⁺ transfer result in mitochondrial energetic failure.

Source: Communications Biology

DOI: 10.1038/s42003-026-09691-y

Institutions: University of Turin, University of Brescia, Broad Institute, Boston Children's Hospital, Harvard University, Manton Center for Orphan Disease Research, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, Leibniz Institute for Analytical Sciences - ISAS, University of Pavia, Fondazione IRCCS Istituto Neurologico Carlo Besta, Istituto Giannina Gaslini, LMU Klinikum, Medical Genetics Center, Ludwig-Maximilians-Universität München, University of Cambridge, Essen University Hospital, Stiftung Universitätsmedizin Essen, University of Duisburg-Essen, University of Colorado Anschutz, University of Colorado Denver, Children's Hospital of Eastern Ontario, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Language: English

Topic: Hereditary Neurological Disorders

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,190

Funders: Compagnia di San Paolo, Wellcome Trust, National Institute for Health and Care Research, Department of Health and Social Care, Fondazione Telethon, Evelyn Trust, Associazione Italiana per la Ricerca sul Cancro, Deutsche Gesellschaft für Muskelkranke, Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, Manton Center for Orphan Disease Research, Boston Children's Hospital, Medical Research Council, Addenbrooke's Charitable Trust, Cambridge University Hospitals, European Regional Development Fund, NIHR Cambridge Biomedical Research Centre

OpenAlex ID: W7128926628