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Investigating the role of lipid dysfunction in mitophagy

Show simple item record 2022-06-15T11:13:47Z 2022-06-15T11:13:47Z 2022-06-15
dc.title Investigating the role of lipid dysfunction in mitophagy en
ethesis.faculty Lääketieteellinen tiedekunta fi
ethesis.faculty Faculty of Medicine en
ethesis.faculty Medicinska fakulteten sv
ethesis.faculty.URI Helsingin yliopisto fi University of Helsinki en Helsingfors universitet sv
dct.creator Naddafi, Seyedehshima
dct.issued 2022 und
dct.abstract 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. en
dct.subject mitophagy
dct.subject DGAT1
dct.subject Iron
dct.subject lipid droplet
dct.subject metabolism
ethesis.language englanti fi
ethesis.language English en
ethesis.language engelska sv
ethesis.supervisor Dr. Thomas McWilliams, Dr. Fumi Suomi und
ethesis.thesistype pro gradu -tutkielmat fi
ethesis.thesistype master's thesis en
ethesis.thesistype pro gradu-avhandlingar sv
dct.identifier.ethesis E-thesisID:dca96f7e-0d00-438b-a7e5-448d16ab9a5c
ethesis-internal.timestamp.reviewStep 2022-05-05 12:03:53:711
dct.identifier.urn URN:NBN:fi:hulib-202206152738
dct.alternative Lipidihäiriön roolin tutkiminen mitofagiassa fi Cell biology und
ethesis.facultystudyline Cross-disciplinary translational medicine fi
ethesis.facultystudyline Cross-disciplinary translational medicine en
ethesis.facultystudyline Cross-disciplinary translational medicine sv
ethesis.mastersdegreeprogram Translationaalisen lääketieteen maisteriohjelma (Translational Medicine) fi
ethesis.mastersdegreeprogram Master's Programme in Translational Medicine en
ethesis.mastersdegreeprogram Magisterprogrammet i translationell medicin sv

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