biostudies-literatureUnknown20Lee JAK<h4>Introduction</h4>ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.<h4>Results</h4>iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.<h4>Conclusion</h4>Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.Frontiers in cellular neuroscience1731669https://www.ebi.ac.uk/biostudies/studies/S-EPMC12933941biostudies-literatureC9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.PMC12933941Moutin CLee JAKFerraiuolo LGranger SShaw AShaw PJMortiboys HAllen SPRoome KfalseC9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.<h4>Introduction</h4>ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.<h4>Results</h4>iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.<h4>Conclusion</h4>Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.2026-01-01T00:00:00Z20262026-07-14T09:21:58.764Z2026-07-14T03:04:12.62ZS-EPMC129339414175735010.3389/fncel.2026.1731669