Dealing with damaged lysosomes: Impact of lysosomal membrane stability in health and disease

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Eriksson, Ida,1985-Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten (författare)

Dealing with damaged lysosomes : Impact of lysosomal membrane stability in health and disease

BokEngelska2022

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Linköping :Linköping University Electronic Press,2022
110 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:liu-184056
ISBN:9789179291785
ISBN:9789179291792
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-184056URI
https://doi.org/10.3384/9789179291792DOI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Serie

Linköping University Medical Dissertations,0345-0082 ;1799

Anmärkningar

Forskningsfinansiärer: Astrid och Bengt Anderssons minnesfond, Borgholm Rotary Klubbs fond för onkologisk forskning, Bröderna Karlssons fondför medicinsk forskning, Familjen Carl och Albert Molins i Motala minne, Ingrid Svensson forskningsstiftelse, Lions forskningsfond mot folksjukdomar, Ssk Siv Olssons forskningsstiftelse, US Stiftelse för medicinsk forskning, samt Östgötaregionens Cancerfond. Den har även gjorts möjlig med hjälp av projektanslag från Cancerfonden, Hudfonden och Vetenskapsrådet.
The lysosome is the main unit for degradation and plays important roles in various cellular processes, such as nutrient sensing, cholesterol regulation and cell death. Consequently, altered lysosomal function contributes to, or even causes, several diseases. Lysosomal membrane permeabilization (LMP) and release of lysosomal content to the cytosol can induce cell death, and is implicated in inflammation and neuronal decline in several neurodegenerative diseases. It has also emerged as a potential target in cancer therapy. Due to the detrimental effects of LMP, cells harbor several mechanisms to protect and prevent lysosomal membrane damage. The aim of this thesis was to elucidate how lysosomal membrane stability and repair mechanisms affect cell death and survival. We find that lysosomal cholesterol is upregulated in response to an increased load of reactive oxygen species in a Parkinson’s disease cell model, and that augmented cholesterol protects from LMP. However, cholesterol also induces accumulation of α-synuclein and inhibits lysosome-mediated degradation, which can destabilize the lysosomal membrane and accelerate the course of disease. Further, we demonstrate that lysosomal membrane damage is counteracted by a calcium-dependent repair mechanism to prevent LMP. Lysosomes damaged beyond repair are instead sequestered in an autophagosome and degraded by intact lysosomes in a process called lysophagy. As a result, small vesicles containing lysosomal membrane proteins are generated, which we believe are used to restore lysosomal function. We show that malignant cells are more sensitive to LMP, and that they differ in their activation of damage-response mechanisms compared to normal cells. Moreover, in malignant cells, the intracellular position of the lysosomes determines the susceptibility to lysosomal damage. Peripherally located lysosomes are less sensitive, and by relocating lysosomes to the perinuclear area in the cell, we can sensitize lysosomes to LMP induction. In summary, this thesis demonstrates the importance of damage-response mechanisms to protect from lysosomal membrane damage and maintain cellular function. It also indicates that targeting of lysosomal stability and repair is a potential therapeutic strategy in both neurodegenerative diseases and in cancer.

Ämnesord och genrebeteckningar

NATURVETENSKAP Biologi Cellbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Cell Biology hsv//eng

Biuppslag (personer, institutioner, konferenser, titlar ...)

Öllinger, Karin,Professor,1962-Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten(Swepub:liu)karol56 (preses)
Wäster, Petra,Assistant Lecturer,1977-Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten(Swepub:liu)petla10 (preses)
Linder, Stig,Professor emeritus,1954-Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten(Swepub:liu)stili13 (preses)
Wüstner, Daniel,Associate ProfessorDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark (opponent)
Linköpings universitetAvdelningen för cellbiologi (creator_code:org_t)

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Av författaren/redakt...: Eriksson, Ida, 1 ...; Öllinger, Karin, ...; Wäster, Petra, A ...; Linder, Stig, Pr ...; Wüstner, Daniel, ...

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NATURVETENSKAP: NATURVETENSKAP; och Biologi; och Cellbiologi

Delar i serien: Linköping Univer ...

Av lärosätet: Linköpings universitet

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