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.
01/03/2024 Dr. Micol Falabella: Department of Neuromuscular Diseases University College London (UK)