Parkinson’s disease-related protein Parkin may rely on another protein called MITOL to repair damaged mitochondria, the small organelles that provide energy to cells and, when defective, can damage brain nerve cells.
Understanding these molecular mechanisms may help improve Parkinson’s therapies that intend to boost Parkin activity.
The study with this finding, “Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL” was published in the Journal of Biological Chemistry.
In a healthy brain, Parkin helps to keep cells alive and reduces the risk of harmful inflammation by repairing damage to mitochondria, which are cells’ “powerhouses.”
Parkin is an enzyme that works by “tagging” damaged mitochondrial proteins for degradation (death) by adding a molecule known as ubiquitin. Ubiquitin is part of a “quality control” system by which cells dispose of damaged, misshapen, or excess proteins.
Parkin’s activity is decreased or absent in many Parkinson’s patients, meaning that damaged mitochondria do not get repaired by Parkin and start to produce harmful molecules, ultimately leading to cellular death.
Other proteins that have similar functions to Parkin can recognize specific amino acid (proteins’ building blocks) sequences on the substances (substrates) in which they act upon. However, Parkin has many substrates that do not appear to have a common amino acid sequence.
To understand Parkin’s selectivity toward a specific sequence, Tokyo Metropolitan Institute of Medical Science investigators investigated whether Parkin could act on mitochondria-targeted artificial proteins (i.e., not found on mammalian cells).
Results revealed that Parkin can act on any protein that contains lysine — an amino acid — but such protein has to be located on the mitochondria’s surface. This means that, unlike its “biological relatives,” Parkin’s activity is not influenced by its substrates’ sequence.
Instead, the control of Parkin activity depends on how this protein is recruited and activated by other proteins.
The team found that Parkin acts more quickly when an ubiquitin molecule is already present, working as a “green-light” for other ubiquitins to be added. Importantly, this first ubiquitin molecule is added by a protein called MITOL, which has never before been associated with Parkinson’s disease.
MITOL is an enzyme present in the membrane of mitochondria that plays a crucial role in the control of this organelle’s morphology.
By targeting MITOL, scientists can potentially increase Parkin’s activity, which may increase efficient mitochondrial repair, and possibly, slow Parkinson’s progression.
“If we achieve upregulation of ‘seed’ ubiquitylation on mitochondria it might accelerate Parkin recruitment and Parkin activation to eliminate damaged mitochondria more efficiently,” Fumika Koyano, of the Tokyo Metropolitan Institute of Medical Science, said in a press release.