When mitochondria—the cell’s power plants—are sick or damaged, they must be cleared away so the cell can survive. For neurons, this type of quality control is critical; the accumulation of sick or damaged mitochondria in brain cells can contribute to neurodegenerative disease.
HMS researchers now have connected this pathway, the malfunction of which has already been associated with Parkinson’s disease and with proteins that are mutated in amyotrophic lateral sclerosis (ALS), the motor-neuron disease also known as Lou Gehrig’s disease. Their findings appeared online September 10 in Molecular Cell.
Mitochondrial damage triggers activation of two proteins—PARKIN and PINK1—that tag a mitochondrion’s surface with chains of ubiquitin, molecules that signal the cell to get rid of the defective organelles. For more than a decade, faulty PARKIN and PINK1 have been linked with early-onset familial forms of Parkinson’s disease, but their role in mitochondrial quality control has only recently been uncovered. In addition, scientists recently have been studying how cells recognize these disposal signals and investigating whether other proteins are involved in the disposal process.
A team of scientists led by Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the HMS Department of Cell Biology, have described how PARKIN and PINK1 work with OPTN and TBK1, proteins that help rid cells of deadly bacteria, to clear cells of damaged mitochondria. They found that PARKIN and PINK1 function early in the disposal process by assembling ubiquitin chains that then are tagged to damaged mitochondria. OPTN and TBK1 bind to these ubiquitin chains to target the damaged mitochondria to the autophagy machinery. Both OPTN and TBK1 are mutated in ALS, but how these proteins contribute to this neurodegenerative disease has remained poorly understood.
The research team also found that the binding of the OPTN-TBK1 complex to the ubiquitin chains promotes TBK1 activation and further activates OPTN’s ubiquitin-binding activity. This establishes a self-reinforced feed-forward mechanism that is critical for the ultimate delivery of mitochondria to the autophagosome, a part of the cell’s system that sequesters and degrades waste material in the cell.
“The surprising thing is that the Parkinson’s genes are functioning upstream of a pathway that’s mutated downstream in motor-neuron disease,” Harper says. “So there is a genetic sensitivity within the pathway that must be different in different cells.”
It may turn out, he adds, that this is a general mechanism that cells use to get rid of a variety of damaged material in different kinds of neurons.