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Liu Xingguo's research group at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences and others have applied high-purity 3D liver organoid technology to the study of hereditary liver diseases for the first time, demonstrating the new pathology of iron death in mitochondrial DNA deletion syndrome (MDS) disease and revealing its The mystery of clinical liver iron overload, and screening of effective drug candidates for inhibiting iron death.
Related research was recently published in Advanced Science.
Mitochondria are one of the most important organelles in eukaryotic cells.
MDS is a major disease that is caused by nuclear gene mutations that maintain mitochondrial DNA synthesis, and the content of mitochondrial DNA is severely reduced.
The pathological phenotype is tissue-specific, and at least 9 gene mutations have been found to cause MDS.
Deoxyguanosine kinase (DGUOK) is an important enzyme for the synthesis of purine nucleotides in mitochondria.
Mutations in this gene are the most common genetic background factor leading to hepatocerebral MDS.
Most of the patients develop symptoms within one month after birth, and the prognosis is extremely poor.
They usually die of severe liver failure within one year.
There is no other effective treatment except liver transplantation.
The liver is the main iron storage organ in the human body.
When iron is overloaded, the liver bears the brunt and becomes the main site of iron toxic attack.
However, the pathological mechanism of such rapid and severe liver failure in DGUOK-mutated MDS patients has not been explained clearly, and there are no effective targeted therapeutic drugs.
In-depth research is urgently needed to find effective treatments.
In order to overcome this medical problem, the researchers reprogrammed the patient's skin fibroblasts into iPSCs and performed CRISPR/Cas9 gene repair to ensure the consistency of genetic background.
Next, the team used high-purity 3D liver organoid differentiation culture technology to eliminate the interference of bile duct cells, and combined with 2D liver-like cell differentiation technology to establish a more powerful and reliable in vitro liver disease model.
The study found that the lack of mitochondrial DNA in the patient's liver cells led to mitochondrial dysfunction, decreased adenine triphosphate synthesis and increased reactive oxygen species.
Both the patient's 3D liver organoids and 2D liver-like cells are more sensitive to iron death caused by iron deposition.
This iron death is an interaction event between mitochondria and lysosome organelles: first, mitochondrial reactive oxygen species surge and glutathione depletion, and then nuclear receptor coactivator 4 mediates the degradation of ferritin in the lysosome, and ferritin The iron released into the cytoplasm causes an increase in lipid peroxidation and eventually leads to iron death of liver cells.
N-acetylcysteine (NAC), the precursor of glutathione screened by further work, can significantly inhibit the iron death of patients' liver cells and can be used as a potential drug candidate.
Related paper information: http://doi.
org/10.
1002/advs.
202004680 Source: China Science News
Related research was recently published in Advanced Science.
Mitochondria are one of the most important organelles in eukaryotic cells.
MDS is a major disease that is caused by nuclear gene mutations that maintain mitochondrial DNA synthesis, and the content of mitochondrial DNA is severely reduced.
The pathological phenotype is tissue-specific, and at least 9 gene mutations have been found to cause MDS.
Deoxyguanosine kinase (DGUOK) is an important enzyme for the synthesis of purine nucleotides in mitochondria.
Mutations in this gene are the most common genetic background factor leading to hepatocerebral MDS.
Most of the patients develop symptoms within one month after birth, and the prognosis is extremely poor.
They usually die of severe liver failure within one year.
There is no other effective treatment except liver transplantation.
The liver is the main iron storage organ in the human body.
When iron is overloaded, the liver bears the brunt and becomes the main site of iron toxic attack.
However, the pathological mechanism of such rapid and severe liver failure in DGUOK-mutated MDS patients has not been explained clearly, and there are no effective targeted therapeutic drugs.
In-depth research is urgently needed to find effective treatments.
In order to overcome this medical problem, the researchers reprogrammed the patient's skin fibroblasts into iPSCs and performed CRISPR/Cas9 gene repair to ensure the consistency of genetic background.
Next, the team used high-purity 3D liver organoid differentiation culture technology to eliminate the interference of bile duct cells, and combined with 2D liver-like cell differentiation technology to establish a more powerful and reliable in vitro liver disease model.
The study found that the lack of mitochondrial DNA in the patient's liver cells led to mitochondrial dysfunction, decreased adenine triphosphate synthesis and increased reactive oxygen species.
Both the patient's 3D liver organoids and 2D liver-like cells are more sensitive to iron death caused by iron deposition.
This iron death is an interaction event between mitochondria and lysosome organelles: first, mitochondrial reactive oxygen species surge and glutathione depletion, and then nuclear receptor coactivator 4 mediates the degradation of ferritin in the lysosome, and ferritin The iron released into the cytoplasm causes an increase in lipid peroxidation and eventually leads to iron death of liver cells.
N-acetylcysteine (NAC), the precursor of glutathione screened by further work, can significantly inhibit the iron death of patients' liver cells and can be used as a potential drug candidate.
Related paper information: http://doi.
org/10.
1002/advs.
202004680 Source: China Science News
