Optic atrophy 1 (OPA1), a GTPase at the inner mitochondrial membrane involved in regulating mitochondrial fusion, stability and energy output, is known to be crucial for neural development: OPA1 heterozygous mice show abnormal brain development, and inactivating mutations in OPA1 are linked to human neurological disorders. Although it known that mitochondria are important for proper neural progenitor cell (NPC) fate decisions, surprisingly little is known about the underlying regulatory mechanisms. Here, using human embryonic and patient-derived induced pluripotent stem cells, we reveal that OPA1 haploinsufficiency causes aberrant nuclear DNA methylation and significantly alters the transcriptional circuitry in NPCs. For instance, expression of the forkhead box G1 transcription factor, which is needed for GABAergic neuronal development, is repressed in OPA1 haploinsufficient NPCs. Consequently, OPA1 +/- NPCs cannot give rise to GABAergic interneurons, while formation of glutamatergic neurons is not affected. Taken together, our data reveal that OPA1 controls nuclear DNA methylation and expression of key transcription factors that are needed for proper neural cell specification.