Targeting Mitochondrial DNA May Be Therapeutic Strategy
In Parkinson’s disease, DNA that leaks out of mitochondria — small organelles that generate energy — leads to cell death and inflammation, according to a new study. The finding indicates that getting rid of this mitochondrial DNA could be a promising therapeutic strategy.
DNA is the molecule used by cells to store the genetic code, which is the instructions for making an organism, be it a bacteria or a human being. In human cells, DNA is stored in two compartments. Most DNA is stored in the nucleus, and there also is some DNA kept in mitochondria, the so-called “powerhouse of the cell.”
The reason mitochondria contain DNA is that these cellular compartments evolved when early cells “ate” bacteria, and then failed to digest them properly. Over time, those bacteria formed a symbiotic relationship with the cells that ate them, ultimately evolving into mitochondria.
Under normal circumstances, cells keep DNA confined to the nucleus and mitochondria, because when there is free-floating DNA within the cytosol (the fluid inside of the cell), it usually means the cell has been infected with a dangerous virus or bacteria. Usually, such abnormal DNA is rapidly degraded by a part of the cell called the lysosome.
In the new study, a team of researchers in Japan found that mitochondrial DNA escapes being destroyed in the lysosome and “leaks” into the cytosol in cellular models of Parkinson’s. In these models, the cells were modified genetically to have mutations in genes that are linked with Parkinson’s, namely PINK1, ATP13A2, and/or GBA.
The team showed this DNA leakage led to cell death, inducing an inflammatory reaction called a type I interferon (IFN) response in the cells. Further experiments revealed the mitochondrial DNA activated IFI16, a protein that normally works to detect DNA from infectious viruses and bacteria and “sound the alarm” within cells.
The team also showed that increasing levels of a protein called DNAse II, which normally helps to degrade abnormal DNA, could reduce the amount of mitochondrial DNA leaking into cells — and that this reduction led to a decrease in cell death and inflammation.
“The results indicated that DNase II overexpression increased the degradation of dsDNA [double-stranded DNA] of mitochondrial origin and reduced the cell death and type I IFN responses caused by the cytosolic dsDNA of mitochondrial origin,” the researchers wrote.
The researchers then examined the role of this leaking mitochondrial DNA in a zebrafish model of Parkinson’s, wherein the fish had mutations in GBA. Consistent with the cell models, the team found evidence of leaking mitochondrial DNA in the fishes’ cells, which was associated with inflammation and cell death.
Using genetic engineering, the team created zebrafish with reduced DNAse II activity, and found that these fishes’ cells had abnormal DNA deposits in the cytosol, as well as neuronal death similar to that seen in Parkinson’s.
The team then engineered GBA-mutant fish to have increased DNAse II activity. Increasing the activity of the DNA-degrading protein “decreased cytosolic dsDNA deposits, rescued neurodegeneration, extended the life span, and improved the movement disorders” in these fish, the researchers reported.
“Our results showed for the first time that cytosolic dsDNA of mitochondrial origin leaking and escaping from lysosomal degradation can induce cytotoxicity both in cultured cells, as well as in zebrafish models of Parkinson’s disease,” Hideaki Matsui, a professor at Niigata University and co-author of the study, said in a press release.
The researchers then examined post-mortem samples of brains collected from people who were diagnosed with idiopathic (of unknown cause) Parkinson’s. They found increased levels of mitochondrial DNA in the cytosol of cells, along with increased levels of the DNA-sensing protein IFI16, in certain brain regions that are affected in Parkinson’s.
These results suggest “that these dsDNA deposits and IFI16 might play important roles in human PD [Parkinson’s disease] pathogenesis,” the team wrote. (Pathogenesis refers to the biological mechanisms by which a disease develops.)
“Based on these results, we propose that the cytosolic leakage of mitochondrial DNA is highly toxic and could be a common and important characteristic of familial and idiopathic PD,” the researchers concluded.
“Strategies that increase DNase II activity and/or inhibit IFI16 activity could represent a potent therapeutic approach for PD,” they added.