Cell-type-specific adaptations to mitochondrial stress underly the neurological presentations of MTRFR mutations

Abstract

Mitochondrial diseases are a group of heterogeneous genetic disorders that exhibit striking tissue specificity. Neurological involvement is among the most consistent features, yet the mechanisms that determine why selective neuronal populations are particularly vulnerable to mitochondrial dysfunction remain poorly understood. Mutations in MTRFR, a mitochondrial ribosome rescue factor, cause a progressive neuromuscular phenotype, but no relevant disease model exists to explain its cell-type-specific pathology. Here, we established the first human iPSC-derived neuronal model of MTRFR loss and identified mechanisms driving differential vulnerability between cortical and motor neurons. Although knockdown led to comparable deficits in mitochondrial translation and OXPHOS across both subtypes, cortical neurons engaged adaptive programs, including dendritic mitochondrial remodelling and heat-shock response activation, that preserved survival. Motor neurons failed to mount these responses and instead displayed apoptotic and inflammatory priming. Pharmacological enhancement of stress adaptation rescued motor neuron survival, indicating that resilience is programmable. These findings provide the first mechanistic evidence that neuronal susceptibility to mitochondrial translation defects is defined by the capacity to activate mitochondrial and cytoprotective stress-response pathways.