A Slc25a46 Mouse Model Simulating Age-Associated Motor Deficit, Redox Imbalance, and Mitochondria Dysfunction

Abstract

Abstract The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knockout, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46−/− mice present segmental premature aging phenotypes characterized by shortened life span of no more than 2 months, obviously defective motor ability, gastrocnemius muscle atrophy, and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to mitochondrial dysfunction, which is mainly manifested in the damaged mitochondrial structure (eg, vacuolar structure, irregular swelling, and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46−/− mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria-based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.