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Lookup NU author(s): Dr Charlotte Alston, Professor Robert TaylorORCiD, Professor Hanns Lochmuller
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid metabolism. Cardiolipin, the signature phospholipid of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesized and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to cardiolipin biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human cardiolipin-related PMDs are not fully characterized. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterized the molecular defects associated with mutant PTPMT1 and confirmed the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterize the functional role of PTPMT1 in cardiolipin homeostasis, we created a ptpmt1 knockout zebrafish. This model had abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired cardiolipin metabolism, highlighting the contribution of aberrant cardiolipin metabolism towards human disease and emphasizing the importance of normal cardiolipin homeostasis during neurodevelopment.
Author(s): Falabella M, Pizzamiglio C, Tabara LC, Munro B, Abdel-Hamid MS, Sonmezler E, Macken WL, Lu S, Tilokani L, Flannery PJ, Patel N, Pope SAS, Heales SJR, Hammadi DBH, Alston CL, Taylor RW, Lochmuller H, Woodward CE, Labrum R, Vandrovcova J, Houlden H, Chronopoulou E, Pierre G, Maroofian R, Hanna MG, Taanman J-W, Hiz S, Oktay Y, Zaki MS, Horvath R, Prudent J, Pitceathly RDS
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2025
Volume: 148
Issue: 2
Pages: 647-662
Print publication date: 01/02/2025
Online publication date: 30/08/2024
Acceptance date: 15/07/2024
Date deposited: 18/02/2025
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awae268
DOI: 10.1093/brain/awae268
Data Access Statement: The authors confirm that the data supporting the findings of this study are available within the article and/or its Supplementary material. These data are available from the corresponding author upon request.
PubMed id: 39279645
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