Transcriptomic and metabolomic analyses reveal cobalt-induced mitochondrial metabolic alterations in human cortical organoids.

The global transition towards carbon-neutral energy systems has prompted a substantial increase in demand for cobalt (Co), making it a crucial component of lithium-ion batteries and advanced industrial materials. The widespread use and limited biological elimination of Co raises growing concerns regarding potential neurodevelopmental toxicity, yet the underlying mechanisms remain largely unresolved. Here, cortical organoids obtained from human induced pluripotent stem cells (iPSCs) were subjected to 5 - 20 μM CoCl2 for 28 days, with the integration of whole-transcriptomics, targeted-metabolomics, and microelectrode array (MEA). The present study has shown that Co exposure induced increased dose-dependent neural apoptosis and HIF-1α stabilization, while inhibiting neuronal generation. Multi-omics integration revealed disruption of tricarboxylic acid (TCA) cycle flux and the assembly of the mitochondrial energy metabolism respiratory chain, which may be mediated by long non-coding RNA (lncRNA)-mRNA interaction networks. These molecular and metabolic disturbances were accompanied by impaired oxidative phosphorylation (OXPHOS), reduced mitochondrial functional status, and ATP depletion. Synaptic immunostaining and MEA analysis further demonstrated that there was impaired formation of excitatory synapses and compromised electrophysiological function. Collectively, these findings provide a mechanistic basis for assessing the developmental neurotoxicity risks associated with Co and underscore the significance of epigenetic regulation of metabolic pathways as a plausible contributing factor from a human-relevant model.