Browsing by Subject "Iron"
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(2022)Autophagy is an essential pathway that evolved to sustain cellular integrity by removing damaged and aged organelles. During this process, our cells sense, encapsulate and deliver defective cellular components to the lysosome for destruction. Over the past decade, many laboratories have demonstrated that damaged mitochondria can be selectively eliminated, during a process known as "mitophagy". Mitophagy senses, targets, and engulfs defective mitochondria for elimination via lysosomal hydrolysis. The identification of factors that promote or prevent mitophagy has high therapeutic relevance, particularly those that alter PINK1/Parkin-independent mitophagy. Recent research in the McWilliams lab uncovered a novel role for lipid metabolism in the regulation of PINK1/Parkin-independent mitophagy. Briefly, the team discovered that DGAT1-dependent lipid droplet (LD) biosynthesis occurred several hours upstream of mitochondrial clearance, with LDs accumulation upon iron chelation. LDs accumulate in a DGAT1-dependent fashion as mitochondria are eliminated. Pharmacological or genetic inhibition of DGAT1, restricts mitophagy levels in vitro and in vivo. However, the mechanism that linked defective lipid metabolism to reduced mitophagy remained mysterious. We hypothesized that defective lipid signalling may compromise lysosomal activity leading to reduced levels of mitophagy. Accordingly, my project examined the functional contribution of DGAT-dependent LD biogenesis to lysosomal homeostasis in the context of PINK1/Parkin-independent mitophagy. After first verifying the DGAT1-dependent nature of LD accumulation in human cells, I established assays to investigate lysosomal homeostasis in the context of iron chelation-induced mitophagy. Using a variety of labelling approaches, live cell imaging experiments revealed a significant displacement of endolysosomes upon DGAT1/2 inhibition, in addition to possible alterations in lysosomal dynamics. My data suggest that loss of DGAT1 activity impairs lysosomal homeostasis when iron levels are low. This likely explains the mitophagy impairments and might account for additional phenotypes of impaired cell viability upon DGAT1 inhibition. Changes in lysosomal acidity were inconclusive, indicating further timepoints may need to be analysed to detect transient impairments in hydrolysis. My results emphasize the importance of organelle crosstalk in mitophagy and the emerging role of LDs in cellular integrity. These data further highlight that targeting lipid metabolism may provide a means to sustain efficient mitochondrial turnover.
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(2020)Iron is a trace element but indispensable for all photosynthesizing organisms. It is unevenly distributed in the world’s oceans, limiting production in offshore high nitrogen low chlorophyll (HNLC) seas. The Caribbean Sea periodically receives high amounts of iron-carrying aeolian dust originating in the African desert. This aerosol Fe is estimated to contribute three times as much as riverine input to the total iron in the seawater, a considerable fraction of it being soluble ferrous Fe(II) due to photochemical reactions. It has been hypothesized that the excess iron in the Caribbean Sea is one of the reasons why the Caribbean coral reefs are less resilient to degradation. The algae that are not limited by iron have the potential to efficiently utilize the macronutrients from e.g. anthropogenic sources and overgrow the corals. In this study Fe, N & P enrichment experiments were conducted in situ in Guadeloupe to find out if iron limitation can be detected and to contemplate the role of atmospheric iron and the anthropogenic impact. Sargassum polyceratium and Dictyota spp. (Phaeophyceae) were collected from four locations that had degraded coral reefs with macroalgae growing on them. The samples’ fluorescence was measured using Pulse Amplitude Modulator (PAM) fluoroscope to detect nutrient-induced fluorescence transients (NIFTs), rapid changes in chlorophyll fluorescence caused by nutrient assimilation in the algal specimen. Iron limitation was detected in all of the study locations but it was weak, which gives limited support to the hypothesis about iron deteriorating the Caribbean reefs’ chances against disturbance. Comparison of the locations did not result in differences in iron limitation according to the anthropogenic impact level. The difference was statistically significant in P limitation, the algae from high impact sites expressing greater demand. Ammonium and nitrate enrichments did not result in significant differences, but NH4 limitation did occur, as well as co-limitation of N & P. Iron has an important role in the phosphorus flux in the sediments and high Fe availability benefits N-fixing cyanobacteria. Redox conditions in the sediment control both Fe and P availability in the water column. Nutrient leaching does affect the local nutrient dynamics but the effects of eutrophication depend on both the species and the community. Notable differences in the NIFT responses were detected between the species that may indeed exert differing nutritional strategies. Coral reef ecosystem complexity emphasizes the importance of timing as well as consistence in quantification of the environmental parameters. The applicability of NIFT results would improve if they were combined with nutrient concentrations data. The fluorescence method appears to be useful in studying iron limitation but more research on iron-induced NIFTs is needed.
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