The accumulation of damaged mitochondria causes the death of dopaminergic neurons. The Parkin-mediated mitophagy pathway functions to remove these mitochondria from cells. Targeting this pathway ...represents a therapeutic strategy for several neurodegenerative diseases, most notably Parkinson's disease. We describe a discovery pipeline to identify small molecules that increase Parkin recruitment to damaged mitochondria and ensuing mitophagy. We show that ROCK inhibitors promote the activity of this pathway by increasing the recruitment of HK2, a positive regulator of Parkin, to mitochondria. This leads to the increased targeting of mitochondria to lysosomes and removal of damaged mitochondria from cells. Furthermore, ROCK inhibitors demonstrate neuroprotective effects in flies subjected to paraquat, a parkinsonian toxin that induces mitochondrial damage. Importantly, parkin and rok are required for these effects, revealing a signaling axis which controls Parkin-mediated mitophagy that may be exploited for the development of Parkinson's disease therapeutics.
YchM is the sole E. coli member of the SLC26 superfamily of anion transporters, which are characterized by an N-terminal transport domain and a C-terminal cytosolic STAS (Sulphate Transporter and ...Anti-Sigma factor antagonist) domain. In a previous study, the STAS domain of YchM co-purified and crystallized with acyl carrier protein (ACP). In this study, analysis of the ACP-STAS interaction using isothermal titration calorimetry (ITC) showed that the 4’phosphopantetheine of ACP and R523 and R527 of the STAS are crucial for binding. The binding constant for the ACP-STAS interaction was found to be 0.7 +/- 0.1 µM. The potential role of YchM for pH regulation and fatty acid degradation studied in vivo indicated that a) YchM does not provide selective advantage for growth in alkaline pH and b) YchM was not essential for cell growth, even when fatty acids were the sole carbon source.
YchM is the sole E. coli member of the SLC26 superfamily of anion transporters, which are characterized by an N-terminal transport domain and a C-terminal cytosolic STAS (Sulphate Transporter and ...Anti-Sigma factor antagonist) domain. In a previous study, the STAS domain of YchM co-purified and crystallized with acyl carrier protein (ACP). In this study, analysis of the ACP-STAS interaction using isothermal titration calorimetry (ITC) showed that the 4’phosphopantetheine of ACP and R523 and R527 of the STAS are crucial for binding. The binding constant for the ACP-STAS interaction was found to be 0.7 +/- 0.1 μM. The potential role of YchM for pH regulation and fatty acid degradation studied in vivo indicated that a) YchM does not provide selective advantage for growth in alkaline pH and b) YchM was not essential for cell growth, even when fatty acids were the sole carbon source.
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