Mitochondrial protein synthesis deficiency tied to fetal anemia microbiologystudy

A research team from the International Research Center for Medical Sciences (IRCMS) at Kumamoto University has identified a novel mechanism linking fetal anemia to disrupted intracellular iron distribution due to impaired mitochondrial protein synthesis.

In this study, a mouse model with a knockout of the mitochondrial tRNA modification enzyme (Mto1) exhibited defective mitochondrial protein synthesis, revealing a previously unknown molecular mechanism. These findings could enhance our understanding of iron-related diseases and open the door to new therapeutic approaches.

The team was led by Dr. Tatsuya Morishima (Lecturer, Wakakusu researcher at IRCMS), and Prof. Hitoshi Takizawa. The research was published in Science Advances.

Study overview

Most of the proteins are synthesized in the cytosol. However, a very small proportion is synthesized within the mitochondria, which are essential for energy production. Traditionally, the protein synthesis in mitochondria has been considered primarily responsible for ATP production. Mitochondrial tRNAs undergo diverse chemical modifications that are post-transcriptionally introduced by tRNA modification enzymes, and these chemical modifications play a crucial role for efficient protein synthesis.

One key enzyme in this process is MTO1, which facilitates mitochondrial protein synthesis by modifying mitochondrial tRNAs. It is known as an important enzyme indispensable for survival, and mutations in MTO1 gene have been associated with severe anemia in patients. However, it remains unknown whether impaired mitochondrial protein synthesis causes hematological disorders.

Key findings

To investigate this, the team generated a mouse model in which the MTO1 gene was knocked out exclusively in hematopoietic cells. These mice all died before birth, and their fetal development was marked by severe anemia. Since blood cell production primarily occurs in the fetal liver, the team analyzed these fetal liver cells and found that mitochondrial OXPHOS (oxidative phosphorylation) complex formation was severely impaired in Mto1 knockout cells.

The OXPHOS complexes normally incorporate various forms of iron into their structures, but in these knockout cells, the intracellular distribution of iron was severely imbalanced. Mitochondrial iron levels decreased, while cytosolic iron levels significantly increased.

The excessive cytosolic iron stimulated the overproduction of heme, a major component of hemoglobin important for oxygen transport in red blood cells. Subsequently, the surplus accumulation of heme induced cellular stress to the red blood cells, ultimately resulting in anemia. This disruption in intracellular iron distribution due to impaired mitochondrial protein synthesis provides a new understanding of the molecular basis for fetal anemia.

This study reveals a previously unrecognized role of mitochondrial protein synthesis in maintaining proper intracellular iron distribution by ensuring proper formation of mitochondrial OXPHOS complexes. Disruption of this process can lead to lethal anemia in the fetal stage. These findings not only highlight a novel molecular mechanism that could advance our understanding of iron-related diseases, but also pave the way for novel therapeutic strategies.