Key result
CPVT-linked RyR2 mutations drive mitochondrial Ca2+ overload and impair neurite outgrowth in dopaminergic neurons.
Why the study?
The pathological relationship between RyR2 mutation-induced Ca2+ dysregulation and ASD pathology remains unclear, particularly its dopaminergic pathological role.
RyR2 hyper-activation-induced mitochondrial Ca2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing dopaminergic neuron development and linking CPVT-related mutations to ASD pathology.
May link RyR2 mutations to ASD via neuronal oxidative stress; leaves open validation in human models and therapeutic targeting.
Type 2 ryanodine receptor (RyR2), a Ca 2+ release channel located in the endoplasmic reticulum (ER) membrane, expresses catecholamine-induced polymorphic ventricular tachycardia (CPVT), and is a potential risk factor of autism spectrum disorder (ASD). However, the pathological relationship between RyR2 mutation-induced Ca 2+ dysregulation and ASD pathology remains unclear. This study examined the association between CPVT-related RyR2 mutations and ASD pathology to determine its dopaminergic pathological role in ASD. Patient-derived stem cells from human exfoliated deciduous teeth were obtained from a boy with comorbid CPVT and ASD, and differentiated to dopaminergic neurons (RyR2-DNs). Two heterozygous missense mutations were identified in RyR2 : c.9910C>G, p.Q3304E in exon 69 and c.14222C>T, p.A4741V in exon 99 (RyR2 69/99 ). RyR2-DNs showed cytosolic and mitochondrial Ca 2+ accumulation, and impaired neurite outgrowth, suggesting that RyR2 69/99 is a gain-of-function mutation that promotes Ca 2+ release from the ER and attenuates neurite development. RyR2-DNs also exhibited increased mitochondrial reactive oxygen species along with impaired mitochondrial oxidative phosphorylation. These mitochondrial abnormalities and neurite outgrowth were managed by pharmacological intervention of mitochondrial Ca 2+ accumulation. Thus, RyR2 hyper-activation–induced mitochondrial Ca 2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing DN development and dopaminergic dysregulation in ASD.
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Ito et al. (2026) studied Catecholamine-induced polymorphic ventricular tachycardia (CPVT) and autism spectrum disorder (ASD) (n=1). RyR2 gain-of-function mutations (c.9910C>G, p.Q3304E and c.14222C>T, p.A4741V) was evaluated on Cytosolic and mitochondrial Ca2+ accumulation, neurite outgrowth, mitochondrial reactive oxygen species, and mitochondrial oxidative phosphorylation. RyR2 gain-of-function mutations from a patient with CPVT and ASD caused mitochondrial Ca2+ overload, oxidative stress, and impaired neurite outgrowth in derived dopaminergic neurons.
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