FROM MITOCHONDRIA TO MOTOR NEURONS FAILURE : MITOPHAGY DYSREGULATION IN CHCHD10-ASSOCIATED AMYOTROPHIC LATERAL SCLEROSIS & FRONTOTEMPORAL DEMENTIA

Neurons require efficient mitochondrial trafficking and turnover to provide high energy demands. Damaged mitochondria can become toxic and must be removed through mitophagy, a key mitochondrial quality control process.
The identification of the p.S59L variant in the mitochondrial protein CHCHD10 provided the first genetic evidence that mitochondrial dysfunction can trigger motor neuron (MN) disease within the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum (Bannwarth et al.,2014). In Drosophila, expression of CHCHD10 p.S59L variant induces chronic activation of PINK1-mediated mitophagy, while PINK1 inactivation rescues mitochondrial network fragmentation (NamChulKim et al.,2021). This project aims to determine whether impaired mitophagy contributes to MN degeneration.
We generated Chchd10^S59L/+ mice that reproduce key ALS and FTD features. To visualize mitophagy in vivo, these mice were crossed with MitoQC reporter mice. To go further, mitophagy was analyzed in spinal motor neurons derived from iPSCs of CHCHD10^S59L/+ patients.
In Chchd10^S59L/+_MitoQC mice, mitophagy was strongly increased in several energy-demanding tissues. In contrast, mitophagy levels in motor neurons and at neuromuscular junctions, two key targets in ALS and FTD, remained unchanged compared to controls. This indicates a selective impaired mitophagy in tissues linked with the pathology. Consistently, patient-derived motor neurons were resistant to both basal and induced mitophagy.
These findings suggest that defective mitophagy in vulnerable tissues may promote the accumulation of damaged mitochondria and contribute to motor neuron degeneration. Ongoing work aims to understand why CHCHD10 p.S59L motor neurons are refractory to mitophagy and whether modulate this pathway could limit neurodegeneration.