Elesclomol-Mediated Alterations of Liver Metabolism in the Context of Mouse Mblac1 Disruption

This study investigates metabolic alterations in Mblac1 knockout (KO) and wild-type (WT) mice using 3D cryo-imaging and redox ratio (RR) analysis to assess the effects of Mblac1 disruption and elesclomol (ES) treatment on liver mitochondrial function. We repeated a prior study where the liver RR of 10-12 week only mice was reduced (46.32%) in KO compared to the WT group. Based on recent findings that deletion of swip-10, the C. elegans ortholog of Mblac1, leads to a systemic loss of mitochondrial function via diminished copper (Cu(I)) homeostasis, we examined the potential for normalization of Mblac1 KO R/R via treatment of these mice with elesclomol (ES), an organic mitochondrial Cu chaperone found to minimize effects of impaired distribution of Cu(I) in a Menkes disease mouse model. In this study, we also found a significant metabolic difference (31.99%) comparing livers of KO and WT groups. Mblac1 KO mice injected with ES demonstrated a significant increase of 33.72% in liver RR values versus WT mice injected with vehicle, amounting to a 47.29% recovery of RR . Our findings support the requirement of MBLAC1 protein to regulate in vivo mitochondrial function via maintenance of Cu(I) homeostasis and the demonstration of a potential therapeutic route for treatment of individuals with MBLAC1 deficiency.