Transcriptome analysis reveals a new insights toward molecular mechanisms of Methylmalonic acidemia in hepatocytes

Abstract

Abstract Background: The overabundance of methylmalonic acid due to the mutation of methylmalonyl-CoA mutase in the mitochondria contributes to hepatocyte damage, impacting various functions, especially energy metabolism. Our study focuses on analyzing transcriptomic alterations induced by methylmalonic acid to elucidate novel mechanisms through which the deficiency of methylmalonyl-CoA mutase causes cellular damage. Results: In this study, we observed that excessive accumulated methylmalonic acid inhibited endoplasmic reticulum (ER)-phagy by downregulating the expression of the ER-phagy receptor FAM134B. This inhibition coincided with an increase in extracellular Ca2+ influx, which aimed to counterbalance the insufficient Ca2+ levels within the overloaded ER. In addition, methylmalonic acid accumulation in hepatocytes triggered ER stress, initiating unfolded protein response via IRE1α-XBP1 pathway. This response aimed to eliminate misfolded proteins and restore ER homeostasis. Moreover, ER stress and increased Ca2+ levels in the cytoplasm activated autophagy, facilitating the degradation misfolded proteins and the affected organelles. The persistent presence of methylmalonic acid hindered mitophagy by inducing the expression of BCL2L1, leading to the accumulation of dysfunctional mitochondria in hepatocytes, thereby exacerbating cellular damage. Conclusions: Our study delves into the impact of methylmalonic acid on hepatocyte functions, shedding light on the interplay between ER-phagy, ER stress, disturbances in Ca2+ flow and mitophagy. By examining these intricate mechanisms, our research unveils promising, previously unexplored therapeutic targets for methylmalonic acidemia.