Abstract
Abnormal development of central nervous system (CNS) caused by neural tube defects (NTDs) is not only remained the major contributor in the prevalence of stillbirths and neonatal deaths, but also represents a significant cause of lifelong physical disability in the surviving infants. Ethionine is a non-proteinogenic amino acid and antagonist of methionine. Methionine cycle is essential for the elimination of reactive oxygen species (ROS), while lysosomes are involved in the initiation of autophagy. However, its role in ethionine-induced cell death in neural tube defects, still need to be explored. In this study, we investigated the effect of ethionine on NTDs as well as the underlying mechanism involved in this process. Following the establishment of NTDs model using ethionine-induced C57BL/6 mice, ethionine was intraperitoneally injected at a dose of 500 mg/kg in E7.5. Our study revealed that ethionine has induced mitochondrial apoptosis in NTDs by reducing mitochondrial autophagy both in vivo and in vitro. These results provided a possible molecular mechanism for redox regulation of autophagic process.
Highlights
The death and disabilities followed by the central nervous system (CNS) diseases are always a major public health concern [1]
We investigated the effect of ethionine on PINK1-Parkin-mediated mitochondrial autophagy, which showed that mitochondrial proteins including PINK1 and Parkin were downregulated in ethionine treatment group compared with control one (Figure 7B)
Our findings suggested that methionine cycle inhibitor-ethionine has increased reactive oxygen species (ROS) formation, reduced Mitochondrial membrane potential (MMP) and enhanced lysosomal alkalization, decreased expression of lysosomal cysteine-Cathepsin B (CTSB) which further suppressed mitochondrial autophagy degradation and induced cell apoptosis in neural tube closure
Summary
The death and disabilities followed by the central nervous system (CNS) diseases are always a major public health concern [1]. Neural tube defects (NTDs) are the most common and serious birth defects of CNS resulted due to unclosed or partially closed neural tube. Lots of results showed that folic acid deficiency contribute significant risk to NTDs development [3]. Folic acid has emerged as a new therapeutic substance against NTDs [4], it cannot prevent all types of NTDs. it is urgent to develop a new effective intervention to prevent NTDs. Systemic study is the first step to uncover the potential therapeutic targets for NTDs induced by folic acid deficiency and its specific mechanism of action needs to be investigated
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