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. One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Disruption to genes involved in CL biosynthesis and remodelling has recently been associated with PMD. However, the pathophysiological mechanisms that underpin human CL-related disorders are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1 with a complex neurological and neurodevelopmental syndrome. Using patient-derived fibroblasts and skeletal muscle tissue, together with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 function has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and oxidative phosphorylation deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, emphasising the contribution of aberrant CL metabolism towards human disease and its importance in neurodevelopment.
E-mail: m.falabella@ucl.ac.uk
1 Marzo, 2024 - ore 15:00
Dr. Micol Falabella: Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK
m.falabella@ucl.ac.uk
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