Quality control of mitochondria seen as compromised in Parkinson’s
Problems likely to impede production of energy necessary for cells
Problems in quality control processes that support the health and function of mitochondria, crucial for cellular energy, are evident in nerve cells of people with Parkinson’s disease, a study showed.
Mitochondrial recycling and protein balance were particularly impaired, which may impede energy production and lead to the early nerve cell death that causes Parkinson’s, the researchers suggested.
The study, “Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins,” was published in the journal npj Parkinson’s Disease.
Problems with mitochondria, cells’ energy source, known in Parkinson’s
Nerve cell loss in Parkinson’s disease is associated with the impaired functioning of mitochondria, the structures in cells that generate energy. However, the underlying mechanisms of mitochondrial dysfunction in Parkinson’s are not fully understood.
Mitochondria have a surveillance system called mitochondrial quality control (MQC), which helps to maintain their proper workings through molecular balance and an ability to adapt to damage.
MQC involves signaling pathways between the nucleus and mitochondria, the regulation of protein folding, and the degradation of misfolded proteins. Mitochondrial joining (fusion), splitting (fission), and mitophagy, the clearing of misfolded or otherwise dysfunctional mitochondria from cells, also are part of quality control.
A team led by scientists at Newcastle University, in the U.K., measured a group of proteins involved in MQC machinery in brain tissue samples from eight deceased Parkinson’s patients. Samples from 11 people with no neurological condition as a control group, and six others with mitochondrial disease to help identify changes specific to Parkinson’s, also were tested.
Researchers used imaging mass cytometry to measure protein abundance at the single nerve cell level.
Eight of 15 proteins with quality control duties lacking in patients’ cells
Compared with controls, significant decreases in the abundance of eight of the 15 MQC signaling proteins were observed in nerve cells from Parkinson’s patients.
The largest decrease was in PHB1 (protein folding), followed by PINK1 (mitophagy), MFN2 (mitochondrial structure), and HSP60 (protein folding). Other proteins involved in the mitophagy pathway (Parkin and pUbSer65) also were significantly deficient in Parkinson’s nerve cells, as were two proteins that activate genes associated with quality control processes (SIRT3 and TFAM).
Only two proteins, DRP1 (mitochondrial fission) and MFN2 (mitochondrial structure), were significantly lower in tissue samples from people with mitochondrial disease. No differences in mitochondrial mass were observed between the groups, and age, post-mortem delay, or sex did not affect protein levels.
These findings suggest that “deficiencies in the MQC proteins were overwhelmingly attributed to disease-specific changes,” the researchers wrote.
In control samples, proteins involved in the same pathway/process significantly correlated with each other, and these correlations were maintained in Parkinson’s and mitochondrial disease cases. Overall, the strongest correlations occurred between proteins in Parkinson’s nerve cells rather than in those of controls, suggesting that “the reduction of MQC proteins abundance might be synergistic in [Parkinson’s], they added.
Researchers then investigated whether changes in MQC proteins associated with a deficiency in oxidative phosphorylation, the metabolic pathway in cells that use enzymes to oxidize nutrients and release energy in the form of adenosine triphosphate (ATP).
Two MQC proteins, SIRT3 and PINK1, were significantly increased in nerve cells from controls deficient in complex V, an enzyme complex that directly generates ATP.
In comparison, a significant loss of SIRT3 and PINK1 was evident in the Parkinson’s and mitochondrial disease samples with complex V deficiency, indicating that the “SIRT3-PINK1 pathway, as part of signal transduction cascade that regulate mitochondrial fusion, fission and mitophagy, might fail to adapt to neuronal energy deficits,” the team noted.
Problems with quality control of mitochondria tied to ‘early neuronal death’
Finally, the relationship between changes in MQC proteins and alpha-synuclein was examined. This protein is known to form clumps in the nerve cells of Parkinson’s patients, and it is associated with disease status.
Nerve cells containing alpha-synuclein aggregates showed significant increases in pUbSer65 (mitophagy) and LonP1 and HTRA2, both proteins that degrade unfolded proteins in MQC. This suggested an “inability to turnover mitochondria and maintain mitochondrial proteostasis [protein balance] in Parkinson’s neurons,” the researchers wrote.
“In this study we … interrogate the levels of proteins in three major groups associated with the regulatory machinery of MQC,” they wrote. Disruptions in mitochondrial turnover and protein balance could “exacerbate the impact of oxidative phosphorylation defects,” they added, “leading to early neuronal death in [Parkinson’s disease].”