PINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage.

Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N6-substituted adenosines, such as N6-(2-furanylmethyl)adenosine (known as kinetin riboside) and N6-benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide m-chlorophenyl-hydrazine and niclosamide. Together, this highlights N6-substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.

Accuracy of distraction based lifting criteria for the identification of insincere effort utilizing the under loading method.

BACKGROUND: Distraction based material handling tests are used to measure effort during functional capacity evaluations. OBJECTIVE: To identify validity of effort using the under loading method with the XRTS Lever Arm. Classification of effort between the two sessions (100% effort and estimated 50% effort) was compared with current validity criteria. METHODS: Fifty healthy and asymptomatic subjects were tested under two conditions (100% effort and an estimated 50% effort). Comparisons were made between percent changes from crate lifts to lever arm lifts from three starting heights (0.25 m, 0.38 m and 0.051 m). RESULTS: During the 100% effort sessions, no subject had a mean percent change >20%, a majority of lift comparison >25% or a single lift comparison >30%. The specificity of the current validity criteria is 100%. The under loading method of using the XRTS lever arm was 20% sensitive in identifying an equivocal or invalid test result when subjects gave an estimated 50% effort. CONCLUSIONS: The results indicate the under loading method of distraction based testing is very specific but lacks sensitivity in identifying feigned weakness with asymptomatic, non-injured individuals. The high specificity of the test should eliminate concern of having a false positive for insincere effort during functional testing.