Boosting clearance of mitochondria may help treat Parkinson’s: Study
The process of mitophagy is impaired in the neurodegenerative disease
A study reports that the proteins NAP1 and SINTBAD play a role in regulating mitophagy, a process wherein damaged mitochondria are removed from cells, which is essential for helping them stay healthy. Mitophagy is impaired in Parkinson’s disease.
“Targeting these proteins in [nerve cells] could be a potential avenue to boost mitophagy by lowering the activation threshold, which in turn can promote mitochondrial and neuronal health,” Michael Lazarou, PhD, the study’s co-lead and an associated professor at the Walter and Eliza Hall Institute (WEHI) in Australia, said in a news release. Details of the discovery were described in the study, “Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD,” and published in Nature Structural & Molecular Biology.
Parkinson’s is caused by the loss of nerve cells in the brain that are responsible for making dopamine, a signaling molecule. Reduced dopamine signaling gives rise to most disease symptoms.
Although the mechanisms that drive nerve cell loss in Parkinson’s aren’t fully understood, the dysfunction of mitophagy, a process that degrades damaged mitochondria, the cell’s energy source, is thought to have a role.
PINK1 and PRKN (or PARK2) are genes that encode proteins that detect mitochondrial damage, and mutations in these genes are associated with early-onset Parkinson’s. In particular, once mitochondria is damaged, PINK1 accumulates in the mitochondrial membrane, recruiting and activating PRKN, which then marks damaged mitochondria with the molecule ubiquitin. This molecule is then recognized by so-called cargo adaptors, proteins that recruit the cellular machinery to degrade damaged mitochondria. The processes that regulate PINK1/PRKN activation are unknown, however.
The role of two proteins in mitochondrial clearance
TBK1 is an enzyme that activates the cargo adaptors OPTN and NDP52 to increase their interaction with ubiquitin, driving mitophagy. The proteins NAP1, which is also known as AZI2, and SINTBAD interact with TBK1.
Lazarou’s research team, collaborating with scientists at the University of Vienna in Austria, investigated the roles of NAP1/SINTBAD in PINK1/PRKN-dependent mitophagy.
Experiments revealed NAP1/SINTBAD initially blocked the activation of PINK1/PRKN-mediated mitophagy by competing with OPTN for TBK1-binding.
“NAP1/SINTBAD initially set a threshold for mitophagy activation by constraining TBK1 activation via the mitophagy receptor OPTN,” the researchers said.
When mitochondrial damage was severe enough, however, NDP52 recruited NAP1/SINTBAD to the mitochondrial surface, effectively removing the blockade between OPTN and TBK1. This allowed more TBK1-mediated activation of cargo adaptors, which promoted mitophagy via the recruitment of the cellular machinery to degrade damaged mitochondria.
Thus, results showed “NAP1/SINTBAD transition into a supportive role, acting as cargo co-receptors that bolster NDP52-driven mitophagy,” the researchers wrote. “Our study uncovers an unexpected additional layer of regulation governing mitophagy initiation and expands our understanding of the complex interplay among various components involved in maintaining mitochondrial quality control.”
“This additional layer may enable cells to respond better to cellular demands and may offer new opportunities for developing new therapeutic strategies aimed at modulating mitophagy in various pathological conditions associated with mitochondrial dysfunction,” they noted.
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