Friedrich ataxia (FRDA), the most common inherited ataxia, is a life shortening autosomal recessive neurodegenerative disease caused by a genetic deficiency of the mitochondrial protein frataxin. Mitochondrial dysfunction and dysregulated Ca²⁺ homeostasis have been implicated in FRDA. ER-mitochondria Ca²⁺ transfer is crucial for cell bioenergetics and survival, and is tightly controlled by IP₃R-GRP75-VDAC1-MCU Ca²⁺ regulation axis at the Mitochondria-Associated ER membranes (MAMs). However, the involvement of endoplasmic reticulum (ER)-mitochondria Ca²⁺ signal pathways in FRDA remain largely unknown.

We examined the levels of IP3Rs and their interactions with GRP75 using Western blot analysis, co-immunoprecipitation assays and immunohistochemical staining, and the ultrastructures of ER, mitochondria and ER-mitochondria contacts using transmission electron microscopy in the cerebellum of KIKO mice. MAMs were isolated from mouse brains and examined for the alterations in IP₃R-GRP75-VDAC1-MCU Ca²⁺ regulation axis.

In wild-type mice, IP₃R1/3 are abundantly and predominantly expressed in the soma and dendrites of cerebellar Purkinje neurons. IP₃Rs interact with GRP75 in cerebellar homogenates, demonstrating the physiological presence of IP₃Rs-GRP75 protein tethering complex in cerebellum. In KIKO mice, the levels of IP₃Rs and their interactions with GRP75 are significantly decreased in cerebellar homogenates, suggesting impaired IP₃R-GRP75 Ca²⁺ signal pathways. Furthermore, the ultrastructural studies show that the number and size of mitochondria, ER and ER-mitochondria contacts are significantly decreased in cerebellar Purkinje neurons of KIKO mice. Moreover, in the isolated MAM fractions of mouse brains, levels of IP3Rs, GRP75, VDAC1, MCU and MICU1/2 and MFN2 are significantly decreased in KIKO mice.