MSTO1 modulates RAD51 activity to safeguard mitochondrial DNA integrity and control immune responses.

Pathogenic MSTO1 mutations cause cerebellar ataxia and congenital myopathy, yet their molecular mechanisms remain poorly understood. This study identifies MSTO1 as a crucial regulator of mitochondrial genome integrity through direct interaction with RAD51. MSTO1 deficiency enhances RAD51 binding to mitochondrial DNA (mtDNA), disrupting mtDNA replication and causing mtDNA damage. This interaction, mediated by the conserved FxxA motif, specifically regulates RAD51's mitochondrial activity without affecting its nuclear roles. Loss of MSTO1 impairs mitochondrial membrane potential, reduces mtDNA content, and increases susceptibility to oxidative stress. Furthermore, MSTO1 deficiency triggers BAX/BAK-dependent mtDNA leakage, activating the cGAS-STING pathway and driving inflammatory responses. Clinical bioinformatics further link low MSTO1 expression with immune activation in cancers. Our findings establish MSTO1 as a modulator of RAD51 activity within mitochondria, regulating mitochondrial stability and immune responses. This provides insights into MSTO1-related diseases and suggests MSTO1 as a potential target for activating anti-tumor immune responses in cancer cells.