Abstract 2355 New insights into the rescue effect of NMN on the Tafazzin-KO C2C12 cells

Cardiolipin (CL) is the signature phospholipid of the mitochondria and is critical for its function. In humans, defects in the TAFAZZIN gene, which encodes an acyltransferase that remodels CL, cause the severe X-linked disorder, Barth syndrome (BTHS). It has been previously shown that NAD+ precursors, such as nicotinamide mononucleotide (NMN), improve the mitochondrial function of CL-deficient yeast (crd1Δ) and rescue the depolarization of mitochondria in mouse Tafazzin-KO C2C12 cells (Taz-KO). In addition, the exercise endurance defect in the Drosophila Taz889 mutant is also restored by NAD+ precursors. In this study, we showed that NMN restores the decreased NAD(H) levels in Taz-KO cells. Using a novel methodology, we discovered that NMN rescued the decreased respiratory capacity of Taz-KO cells when cultured in glucose medium, which was not observed previously in seahorse medium. Further investigations suggested that NMN non-specifically reduces lactate production by Taz-KO cells and did not alter increased pyruvate and decreased glutamate production by Taz-KO. In conclusion, the ongoing study identified the rescue effect of NMN on the compromised respiration capacity of Taz-KO cells in a rich glucose medium. The results suggested that the rescue effect of NMN on decreased respiration capacity of the Taz-KO cells are unlikely through altering metabolite levels under the tested conditions. The alternative mechanism of rescuing through sirtuin signaling and increasing mitochondrial biogenesis is under investigation.