Lysosomal stability under the influence of oxidative stress and lipofuscin accumulation

• The lysosome is the cellular organelle responsible for degradation and recycling of macromolecules through hetero- and autophagocytosis. It is generally considered a stable organelle that breaks down only late during cellular degeneration. This study is one in a series aiming to show that lysosomes, on the contrary, are quite vulnerable, especially to mtidative stress. Oxidative stress was applied as hydrogen peroxide or light irradiation.Three different cell types, known to differ considerably in their sensitivity to oxidative stress, were explored with respect to hydrogen peroxide-degradation capacity. The least sensitive comprised the highest degradation capacity, and vice versa. Furthermore, the importance of the iron content of lysosomes was investigated. Iron is known to induce Fenton reactions when reacting with hydrogen peroxide by homolytic cleavage. This creates the very reactive hydroxyl radical which can initiate lysosomal membrane damage. The result, if the oxidative stress is sufficiently pronounced, will be leakage of lysosomal enzymes to the cytosol, with ensuing cellular damage and, maybe, even death. We hypothesise that lysosomes containing the most redox-active iron also are the ones most vulnerable to oxidative stress. Lysosomes in all cell populations were shown to differ normally in iron content, and also in sensitivity to oxidative stress. Exposure to iron was shown to increase the sensitivity of cells to hydrogen peroxide, while the potent iron-chelator deferoxarnine decreased it. For photo-oxidation no such correlation was seen, indicating that the latter damage was mediated by singlet oxygen. However, a clear interlysosomal variation in stability was obvious here as well.As post-mitotic cells grow older, an indigestible material, known as lipofuscin or age pigment, accumulates in their lysosomes. This is commonly considered harmless to the cell, but we have for some time advocated the idea that the accumulation is detrimental. Here we have developed a new method to investigate lipofuscin's impact on cellular and especially lysosomal function. Artificial ceroid/lipofuscin was created through UV-irradiation of subcellular organelles and shown be endocytosed by cells, thereby transforming them to an aged phenotype.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Hälsovetenskap -- Annan hälsovetenskap (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Health Sciences -- Other Health Sciences (hsv//eng)

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MEDICINE

MEDICIN

Medicin

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