Investigating Cell-Type-Specific Vulnerability in Mitochondrial Disease Using Stem Cell-Derived Neuronal Models
Mitochondrial diseases are a group of widely heterogeneous genetic disorders that primarily affect tissues with high energy demands. Although disruption of oxidative phosphorylation is a shared hallmark across these conditions, their clinical manifestations display remarkable tissue specificity, with certain cellular populations showing heightened susceptibility. Neurological involvement is among the most consistent features in these disorders, yet the molecular and metabolic drivers of selective vulnerability in different neuronal subtypes remain poorly understood. In this thesis, I developed human stem cell-derived neuronal models for two nuclear-encoded mitochondrial disorders that impair mitochondrial DNA (mtDNA) replication and translation. The first model examined the selective vulnerability of GABAergic inhibitory interneurons to mutations in the mitochondrial DNA polymerase catalytic subunit POLG, while the second focused on the susceptibility of spinal motor neurons to loss of function of the mitochondrial translation release factor MTRFR. Both models successfully recapitulated the key mitochondrial defects observed in patient-derived cells, including OXPHOS deficiency and mtDNA depletion, while revealing distinct adaptive and pathological responses between neuronal subtypes. MTRFR loss triggered cell-type-specific stress responses. Cortical neurons activated compensatory mechanisms such as mitochondrial remodelling and heat shock protein induction, while motor neurons showed increased apoptosis and inflammatory priming. In POLG mutant neurons, GABAergic interneurons exhibited a rigid, OXPHOS-dependent metabolic profile with limited biosynthetic and redox flexibility, predisposing them to energetic failure under mitochondrial stress. In contrast, glutamatergic neurons displayed greater metabolic adaptability and engagement of compensatory pathways. Together, these findings provide new insights into how intrinsic metabolic shifts and stress-response programs shape selective neuronal vulnerability in mitochondrial disease. By identifying both protective and maladaptive mechanisms, this work offers a framework for developing cell-type-specific interventions aimed at preserving neuronal function and resilience.
iPSC-derived disease modelling, Mitochondria, Mitochondrial diseases, Tissue specificity
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