A Novel Mmachc c.80A>G Mouse Model Reveals the Role of Mitochondrial Dysfunction in Skeletal Muscle in Combined Methylmalonic Acidemia and Homocystinuria

Combined methylmalonic acidemia and homocystinemia (cblC) is an autosomal recessive disorder characterized by aberrant organic acid metabolism. The c.80A > G mutation in the MMACHC gene has been documented in numerous studies and linked to cblC phenotypes. However, this mutation's pathogenic mechanisms remain elusive, as it has not yet been validated through functional studies. In a previous study, we developed a murine model with the Mmachc c.80A > G mutation to elucidate the intricacies of the cblC disorder. Our current investigation delves deeper into the cblC mouse model, revealing persistently elevated levels of methylmalonic acid (MMA) and homocysteine (Hcy) in blood, urine, and tissues. This phenomenon can be attributed to diminished expression of the Mmachc. The survival rate of these model animals was markedly compromised, with altered blood biomarkers and imaging abnormalities mirroring the clinical manifestations of cblC. Further exploration revealed that the accumulation of MMA and Hcy in tissues is not only a consequence of B12-processing but also contributes to mitochondrial dysfunction, which is particularly pronounced in skeletal muscle. Concurrently, the c.80A > G mouse model exhibited disruption of mitochondrial autophagy, resulting in mitochondrial proliferation and impaired ATP metabolism. Notably, MMA emerged as a pivotal factor in cellular energy stress, damage to the mitochondrial respiratory chain and ATPase activity. Collectively, these findings indicate that the c.80A > G mutation plays a significant role in the mitochondrial pathogenesis of cblC by inducing intron retention, thereby providing novel insights into the underlying disease mechanism.