Protein appears as a “guardian” of “preserving cell” energy, making mitochondria safe

Scientists at Johns Hopkins Medicine say they have discovered how a group of proteins associated with Parkinson’s disease and amyotrophic lateral sclerosis are “guardians” of mitochondria, small organelles or subunits in cells that produce and store energy, and have been found in almost all animals and plants.

Scientists say that it was produced by experiments in genetically engineered mice and should improve understanding of the development of Parkinson’s disease – the development of Parkinson’s disease – a chronic and progressive neurodegenerative disease whose causes are unclear. Most experts believe Parkinson’s disease is the result of some combination of genetics and environmental factors.

Abstracts of the researchers’ experiments appeared in the March 20th Journal nature.

The new study, funded by the National Institutes of Health, stems from previous efforts to demonstrate how cells respond to stress, including external pressures such as low oxygen levels and internal pressures, such as nutritional imbalances.

According to Dr. Hiromi Sesaki, Ph.D., a professor of cell biology at Johns Hopkins School of Medicine, who studies how mitochondria grow, divide and Fuse, the organelles are neither too large nor too small to work properly.

Scientists have long known that when mitochondria are damaged when stress is too high or cannot be repaired, they stop fusing, becoming smaller and degraded. Mitochondria are damaged and cells are insufficient. In the brain, stress cells cause neurodegeneration and neuroinflammation.

As a result, cells deploy various methods to protect mitochondria and maintain them in the correct size. For example, cells can repair mitochondria by fusing them together to maintain their genomic material and energy output.

Mitochondria may also divide after growth to maintain their size and quantity or separate damaged parts. However, if mitochondria become too large, they stop fusion, thus preventing the formation of harmful giant mitochondria, which in turn hinders the effective degradation of mitochondria damage.

According to Dr. Miho IIJIMA, a professor of cell biology at Johns Hopkins University School of Medicine, this is one way for cells to cope with mitochondrial size control problems caused by stress or damage, which is to turn on the activity of several proteins. Two proteins Parkin and Pink1 are suspended on the membrane of the mitochondria and act as a pair to allow the mitochondria to fuse or degrade. Abnormalities in Parkin and Pink1 genes are associated with the onset of Parkinson’s disease in humans.

It is well known that another protein associated with amyotrophic lateral sclerosis can also prevent mitochondria from fusion under stress.

Previous mouse studies have shown that when conditions in cells are normal, removed or “knockout”, no one of the genes encoding Parkin, Pink1 and Oma1 proteins lead to abnormalities in mice or mitochondria.

However, IIJIMA and SESAKI want to know what happens to mice and their cells if three genes (Parkin, Pink1 and Oma1) were knocked down under normal physiological conditions.

By eliminating Parkin, Oma1 or Pink1 and Oma1, scientists found that double-knockout mice were small and fused excessive, super-large mitochondria in neurons compared to mice with normal versions of the gene.

However, if only one gene is knocked out, the other gene still regulates mitochondrial fusion and the mice have no signs of mitochondrial tumors or dysfunction.

Johns Hopkins medical scientists speculate that mitochondrial fusion is “double-locked.” Since mitochondria have two membranes, closing only one gene may disable one membrane, but not both, while mitochondria can still fuse and stay healthy.

Overall, the research team conducted genetic studies on genetically engineered mice with normal and knockout combinations of three genes and other genes to confirm this conclusion.

“Parkin-Pink1 and Oma1 work in the duo, acting as guardians of mitochondria to ensure that the organelles remain in normal size and function,” Iijima said.

Scientists also measured the energy of the main product of mitochondria: adenosine triphosphate (ATP). Among all the mice studied, they found no significant differences in ATP levels in brain cell samples.

To address this discovery, scientists have studied the immune system responses associated with brain cells more carefully. They found that when the mitochondria are too large, mitochondrial DNA leaks into the cytoplasm, which is the fluid that fills the space inside the cell. This triggers an increase in interferon release, which causes an inflammatory response to the protein.

Scientists plan to advance their work by studying more precisely the leakage of mitochondrial DNA from the organelles when it is too large. They also wanted to identify which cell types respond to neuronal mitochondrial DNA release to induce innate immune responses, with the aim of discovering new insights on the development of Parkinson’s disease and possibly a new target of therapeutic drugs.

This study was supported by the National Institutes of Health (R35GM144103, R35GM131768 and P20GM104320), the Human Aging Project and the Adrienne Helis Malvin Medical Research Foundation. Sesaki is an Ethan and Karen Leder CIM/HAP scholar.

In addition to Sesaki and Iijima, other scientists who contributed to the research are Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Seth Blackshaw, Anne Le, Valina Dawson and Ted Dawson from Johns Hopkins; Pedro Quirós and Carlos López-otín from the University of Oviedo in Spain; Thomas Langer from the Max Planck Institute in Germany; David Chan from the California Institute of Technology.