A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis

Brunk, Ulf T.; Jones, Charles B.; Sohal, Rajindar S.

doi:10.1016/0921-8734(92)90042-n

Cited by 261 publications

(139 citation statements)

References 16 publications

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“…Although non-degradable material can theoretically form in any cellular compartment and then be delivered to lysosomes through autophagy, there are good reasons to believe that lysosomes themselves are the principal sites at which lipofuscin is produced [75]. As a result of autophagy, lysosomes contain a wide variety of subcellular structures, most importantly mitochondria, which are rich in lipidaceous membrane components and iron-containing proteins, such as cytochrome c. The formation of lipofuscin from mitochondrial components is supported by the presence of the ATP synthase subunit c in age pigment granules [76].…”

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

“…Such low-mass iron is partially in the ferrous (FeII) state, due to an abundance in lysosomes of the reducing amino acid cysteine, a product of protein degradation. In the reducing acidic milieu of lysosomes, iron-catalysed peroxidation is particularly effective [79], and lipofuscin forms by complexing of aldehydes (developed secondary to fragmentation of lipid peroxides) with free amino groups of protein fragments [29,75]. Major factors enhancing lipofuscin formation are: a high level of autophagic activity; the pronounced formation of hydrogen peroxide (oxidative stress) or insignificant cytosolic degradation of the hydrogen peroxide that has been formed; and high concentrations within the lysosomes of low-mass redox-active iron [29,75].…”

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

“…Such influx, if significantly increased above normal levels, as is the case during a period of oxidative stress, may also result in the formation of hydroxyl radicals or reactive ironcentred radicals, in such numbers that the stability of the lysosomal membrane is jeopardized [11,29,75]. Obviously lysosomes and mitochondria are mutually dependent, creating a system that we believe is of great importance for apoptosis and postmitotic ageing [5,16].…”

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

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Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

262

210

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As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death.

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Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

Section: Mechanisms Of Lipofuscin Accumulationmentioning

confidence: 99%

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Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

262

210

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“…Since humans lack mechanisms for iron elimination, except menstrual bleeding and removal of apoptotic enterocytes and some macrophages by defecation, iron uptake is strictly regulated (vide infra). Nevertheless, over time, iron as well as some other heavy metals, accumulate, especially in postmitotic cells such as neurons and myocardial cells (Brun and Brunk, 1973, Brunk et al, 1992, Double et al, 2008). This accumulation is largely associated with the age pigment lipofuscin that forms and remains within the lysomal compartment (vide infra).…”

Section: Introductionmentioning

confidence: 99%

The role of lysosomes in iron metabolism and recycling

Kurz

Eaton

Brunk

2011

The International Journal of Biochemistry & Cell Biology

Self Cite

172

134

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Iron is the most abundant transition metal in the earths crust. It cycles easily between ferric (oxidized; Fe(III)) and ferrous (reduced; Fe(II)) and readily forms complexes with oxygen, making this metal a central player in respiration and related redox processes. However, loose iron, not within heme or iron-sulfur cluster proteins, can be destructively redox-active, causing damage to almost all cellular components, killing both cells and organisms. This may explain why iron is so carefully handled by aerobic organisms. Iron uptake from the environment is carefully limited and carried out by specialized iron transport mechanisms. One reason that iron uptake is tightly controlled is that most organisms and cells cannot efficiently excrete excess iron. When even small amounts of intracellular free iron occur, most of it is safely stored in a non-redox-active form in ferritins. Within nucleated cells, iron is constantly being recycled from aged iron-rich organelles such as mitochondria and used for construction of new organelles. Much of this recycling occurs within the lysosome, an acidic digestive organelle. Because of this, most lysosomes contain relatively large amounts of redox-active iron and are therefore unusually susceptible to oxidant-mediated destabilization or rupture. In many cell types, iron transit through the lysosomal compartment can be remarkably brisk. However, conditions adversely affecting lysosomal iron handling (or oxidant stress) can contribute to a variety of acute and chronic diseases. These considerations make normal and abnormal lysosomal handling of iron central to the understanding and, perhaps, therapy of a wide range of diseases

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“…LF, one of the products of lipid peroxidation, is undegradable and cannot be removed via exocytosis (Brunk et al, 1992). Brunk and Terman (2002) have proposed a possible role for the involvement of OS in LF formation.…”

Section: Discussionmentioning

confidence: 99%

Adaptations of the antioxidant system in erythrocytes of trained adult rats: Impact of intermittent hypobaric-hypoxia at two altitudes

Devi

Subramanyam

Vani

et al. 2005

Comparative Biochemistry and Physiology Part C: Toxicology &

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We have investigated the effects of daily exposure to intermittent hypobaric-hypoxia to two simulated altitudes (5700 m and 6300 m) in adult male rats that had been regularly swim trained in normoxia at sea level prior to exposures. Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) along with the oxidative stress (OS) indices, malondialdehyde (MDA) and protein carbonyl content were measured in erythrocytes and their membranes. Hemoglobin increased in the trained animals exposed to 5700 m and in untrained rats exposed to 6300 m. Osmotic fragility in terms of hemolysis increased in altitude exposed animals. SOD increased in those exposed to 6300 m, while CAT increased in trained rats exposed to 5700 m and to 6300 m unlike in untrained rats where CAT increased only at 6300 m. GSH-Px showed varying degrees of elevation in all animals exposed to both altitudes. Erythrocyte membranes showed significant elevations in malondialdehyde (MDA) at 6300 m, while elevated protein carbonyls were noticeable at both altitudes in whole cells and membranes. These results suggest a positively associated elevation in protein oxidation with altitude in trained rats. At 5700 m, animals were less stressed, unlike at 6300 m, as seen from the magnitude of elevations in the OS indices and from the responses of the antioxidant enzymes. D

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A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis

Cited by 261 publications

References 16 publications

Autophagy, organelles and ageing

Autophagy, organelles and ageing

The role of lysosomes in iron metabolism and recycling

Adaptations of the antioxidant system in erythrocytes of trained adult rats: Impact of intermittent hypobaric-hypoxia at two altitudes

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