Nanoparticles Restore Mitochondrial Function in Mouse Study
A team of researchers has designed nanoparticles able to restore the function of mitochondria — cells’ energy production centers — and improve motor behavior in a mouse model of Parkinson’s disease.
Experiments in cell cultures revealed that the nanoparticles could restore function of reversibly damaged mitochondria and promote the clearance of irreversibly damaged ones, all while leaving healthy mitochondria untouched.
“Our study provides a novel strategy for [Parkinson’s] treatment,” the researchers wrote.
The study, “A novel nanoparticle system targeting damaged mitochondria for the treatment of Parkinson’s disease,” was published in Biomaterials Advances.
Parkinson’s disease is characterized by the loss of dopamine-producing nerve cells in the brain. Mitochondrial dysfunction, which can be reversible or irreversible, is thought to contribute significantly to this cell death.
Treatments targeted at repairing mitochondrial function are a possible therapeutic strategy for Parkinson’s.
Researchers now have developed nanoparticles, small carrier particles, intended to target the dysfunctional mitochondria. These particles contained hyaluronic acid, a natural anti-inflammatory substance found in the fluid surrounding the eyes and joints that has been shown to protect mitochondria and prevent cellular damage resulting from their dysfunction.
To ensure the nanoparticles would be targeted specifically toward dysfunctional mitochondria, the team added an antibody against a protein called PINK-1. PINK-1 accumulates on the surface of damaged mitochondria. The antibodies were intended to attract the nanoparticles to unhealthy mitochondria, leaving healthy ones untouched.
In cell culture experiments, the nanoparticles demonstrated an ability to protect mitochondria against damage and restore their function in nerve cells under stress. The treatment also was protective in cultures of mouse embryonic fibroblasts (MEF) — a type of cell involved in forming connective tissue.
While the nanoparticles showed promise, they were designed to restore normal function only in mitochondria with reversible damage. To enable the nanoparticles to promote the removal of irreversibly damaged mitochondria, the team added another modification.
USP30 is a mitochondrial enzyme that prevents mitophagy, a quality-control mechanism cells use to get rid of faulty or excess mitochondria. Its blockade has been shown to alleviate mitochondrial damage in cell cultures and protect dopamine-producing nerve cells in a fly model.
The team incorporated into the nanoparticles a short-interfering RNA (siRNA) molecule that was designed to bind to the USP30 gene and lower its production of USP30, thereby promoting autophagy and enabling the removal of faulty mitochondria.
The continued presence of the PINK-1 antibody was intended to target this knockdown of USP30 to irreversibly damaged mitochondria.
To test the modified nanoparticles, the team incubated MEF cells in culture with CCCP, a compound that induces mitochondrial damage, then added the nanoparticles.
Results showed that the nanoparticles specifically accumulated in cells with damaged mitochondria, and lowered USP30 levels. Nanoparticles containing the siRNA also partially restored mitochondrial function.
Similarly, in nerve cells undergoing mitochondrial stress in cell cultures, the nanoparticles led to significantly improved mitochondrial function and structure and enhanced cells’ ability to resist damage, improving their survival.
In a mouse model of Parkinson’s, injection of the nanoparticles led to improved motor behaviors and restored mitochondrial structure.
“We successfully designed and developed [nanoparticles] for the treatment of [Parkinson’s] that can target different stages of mitochondrial damage,” the researchers wrote, noting that with their approach healthy mitochondria are left untouched.
“This strategy is expected to overcome the problems associated with the excessive clearance of healthy mitochondria and has great potential for clinical applications,” the team concluded.