ICT2025 - lUTOX 17th International Congress of Toxicology

Date	Time	Local Time	Room	Forum	Session	Role	Topic
2025-10-17	17:50-18:00	2025-10-17,17:50-18:00	Room A - Guojin Hall	Symposium Program （Session）	Young Scientist Lecture 04：Environmental Toxicology and Molecular Toxicology	Speaker	ALKBH5- regulated MICU1 methylation participates in precise mitochondrial degradation induced by cobalt nanoparticles Cobalt nanoparticles (CoNPs) represent an environmental risk factor for Alzheimer’s disease (AD), involving disrupted calcium homeostasis and m6A modification. Using Caenorhabditis elegans, human neuroblastoma SH-SY5Y cells, and C57B/L mice, this study demonstrates that CoNPs upregulate the m6A demethylase ALKBH5, reducing global neuronal m6A levels and specifically on MICU1 mRNA (binding confirmed by molecular docking and RNA-pulldown), leading to increased MICU1 protein. This MICU1 upregulation drives mitochondrial calcium overload, fragmentation, and respiratory dysfunction. On the other hand, we have observed that CoNPs triggered a 2.7-fold increase in the formation of vesicles derived from the inner mitochondrial membrane (VDIM) compared with the control. VDIM enables inner membrane-specific degradation of damaged components—a precision repair mechanism activated by MICU1-mediated injury. Notably, ALKBH5 knockdown exacerbated CoNPs-induced calcium overload and mitochondrial damage, while MICU1 overexpression rescued these defects; VDIM levels correlated directly with MICU1 expression. Taken together, this work is the first to elucidate an epigenetic (m6A/ALKBH5) axis governing mitochondrial calcium homeostasis (via MICU1) and downstream precision repair (VDIM). It reveals a novel CoNPs neurotoxicity pathway relevant to AD pathogenesis, identifying ALKBH5/MICU1 as therapeutic targets and pioneering epitranscriptomic regulation in organelle-specific quality control.

Cobalt nanoparticles (CoNPs) represent an environmental risk factor for Alzheimer’s disease (AD), involving disrupted calcium homeostasis and m6A modification. Using Caenorhabditis elegans, human neuroblastoma SH-SY5Y cells, and C57B/L mice, this study demonstrates that CoNPs upregulate the m6A demethylase ALKBH5, reducing global neuronal m6A levels and specifically on MICU1 mRNA (binding confirmed by molecular docking and RNA-pulldown), leading to increased MICU1 protein. This MICU1 upregulation drives mitochondrial calcium overload, fragmentation, and respiratory dysfunction. On the other hand, we have observed that CoNPs triggered a 2.7-fold increase in the formation of vesicles derived from the inner mitochondrial membrane (VDIM) compared with the control. VDIM enables inner membrane-specific degradation of damaged components—a precision repair mechanism activated by MICU1-mediated injury. Notably, ALKBH5 knockdown exacerbated CoNPs-induced calcium overload and mitochondrial damage, while MICU1 overexpression rescued these defects; VDIM levels correlated directly with MICU1 expression. Taken together, this work is the first to elucidate an epigenetic (m6A/ALKBH5) axis governing mitochondrial calcium homeostasis (via MICU1) and downstream precision repair (VDIM). It reveals a novel CoNPs neurotoxicity pathway relevant to AD pathogenesis, identifying ALKBH5/MICU1 as therapeutic targets and pioneering epitranscriptomic regulation in organelle-specific quality control.