Autophagic degradation of peroxisomes in isolated rat hepatocytes

Luiken, Joost J. F. P.; Berg, Marlene van den; Heikoop, Judith C.; Meijer, Alfred J.

doi:10.1016/0014-5793(92)80596-9

Cited by 65 publications

(46 citation statements)

References 33 publications

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“…In contrast to general (nonselective) autophagy, e.g., observed under nutrient deprivation and leading to the simultaneous degradation of different organelles and cytosolic components (2,6,8,9,16,37,38), selective autophagy is restricted to one type of organelle. For example, in mammalian cells the endoplasmic reticulum or peroxisomes are selectively degraded upon removal of their proliferators (3,20). In the methylotrophic yeasts H. polymorpha and Pichia pastoris, selective degradation of peroxisomes occurs after a shift of cells from methylotrophic to nonmethylotrophic growth conditions or after irreversible inactivation of the organellar function (21,25,27,29,32).…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha

et al. 1995

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We have isolated a collection of peroxisome degradation-deficient (Pdd ؊ ) mutants of the yeast Hansenula polymorpha which are impaired in the selective autophagy of alcohol oxidase-containing peroxisomes. Two genes, designated PDD1 and PDD2, have been identified by complementation and linkage analyses. In both mutant strains, the glucose-induced proteolytic turnover of peroxisomes is fully prevented. The pdd1 and pdd2 mutant phenotypes were caused by recessive monogenic mutations. Mutations mapped in the PDD1 gene appeared to affect the initial step of peroxisome degradation, namely, sequestration of the organelle to be degraded by membrane multilayers. Thus, Pdd1p may be involved in the initial signalling events which determine which peroxisome will be degraded. The product of the PDD2 gene appeared to be essential for mediating the second step in selective peroxisome degradation, namely, fusion and subsequent uptake of the sequestered organelles into the vacuole. pdd1 and pdd2 mutations showed genetic interactions which suggested that the corresponding gene products may physically or functionally interact with each other.In yeasts, peroxisomes develop in response to metabolic needs (23,28). In Hansenula polymorpha, the organelles are strongly induced by methanol and, to a lesser extent, by a number of unusual nitrogen sources, including primary amines. The opposite may also occur: under certain conditions, peroxisomes may be actively degraded after a shift of cells to a new environment in which the organelles become redundant for growth (32).At present, two conditions which lead to a rapid turnover of alcohol oxidase-containing peroxisomes in H. polymorpha are known, namely, a shift of cells from methylotrophic to nonmethylotrophic conditions (29, 32) and irreversible inactivation of the organellar function (21, 27).The degradation process appeared to be energy dependent (29). The peroxisomes are degraded individually by a highly selective autophagic process, and the degradation process appeared to be identical under either of the above conditions. As an initial step, organelles to be degraded were sequestered from the cytosol by a number of membranous layers, closely surrounding the organelle, which most probably were derived from the endoplasmic reticulum; subsequently, hydrolytic enzymes required for the degradation of the microbody contents were supplied by fusion of part of the vacuole with the sequestered organelle (21,27,29,32). The degradation of peroxisomes in H. polymorpha is a rapid process; generally, the total turnover of a single organelle is accomplished within 20 to 45 min (29). However, not all organelles of the peroxisomal population present in one cell are affected: in particular, the large mature peroxisomes are rapidly degraded. These and other results (26) strongly suggest that the organelles destined for degradation are specifically tagged. Recently, we have obtained indirect evidence that the signals, initiating peroxisome turnover, are not directed against the matrix proteins but inst...

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Section: Discussionmentioning

confidence: 99%

Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha

et al. 1995

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“…The accelerated degradation of peroxisomes was sensitive to inhibition by 3-methyladenine, a specific autophagic sequestration inhibitor. Interestingly, the accelerated removal of peroxisomes was prevented by long-chain but not short-chain fatty acids (Luiken et al, 1992). Since long-chain fatty acids are substrates for peroxisomal -oxidation, this indicates that these organelles are removed by autophagy when they are functionally redundant.…”

Section: Specificity Of Macroautophagymentioning

confidence: 97%

“…When hepatocytes from these rats, in which the number of peroxisomes is greatly increased, are incubated in the absence of amino acids to ensure maximal flux through the macroautophagic pathway, peroxisomes are degraded at a relative rate that exceeds that of any other component in the liver cell (Luiken et al, 1992). The accelerated degradation of peroxisomes was sensitive to inhibition by 3-methyladenine, a specific autophagic sequestration inhibitor.…”

Section: Specificity Of Macroautophagymentioning

confidence: 99%

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Blommaart

1997

The Histochemical Journal

204

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SummaryThe rate of proteolysis is an important determinant of the intracellular protein content. Part of the degradation of intracellular proteins occurs in the lysosomes and is mediated by macroautophagy. In liver, macroautophagy is very active and almost completely accounts for starvation-induced proteolysis. Factors inhibiting this process include amino acids, cell swelling and insulin. In the mechanisms controlling macroautophagy, protein phosphorylation plays an important role. Activation of a signal transduction pathway, ultimately leading to phosphorylation of ribosomal protein S6, accompanies inhibition of macroautophagy. Components of this pathway may include a heterotrimeric G i3 -protein, phosphatidylinositol 3-kinase and p70S6 kinase. Recent evidence indicates that lysosomal protein degradation can be selective and occurs via ubiquitin-dependent and -independent pathways.

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“…96 The mammalian example of pexophagy was first demonstrated in the liver following the treatment of clofibrate or phthalate esters, both peroxisome proliferators that activate PPAR␣. 97,98 Abundant amounts of autophagosomes were found in the livers of treated rats. In addition, pexophagy as monitored by the degradation of peroxisomal enzymes could be suppressed by 3-MA.…”

Section: Autophagic Degradation Of Er-reticulophagy (Erphagy)mentioning

confidence: 99%

Autophagy in the liver

2008

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A great part of our current understanding of mammalian macroautophagy is derived from studies of the liver. The term "autophagy" was introduced by Christian de Duve in part based on ultrastructural changes in rat liver following glucagon injection. Subsequent morphological, biochemical, and kinetics studies of autophagy in the liver defined the basic process of autophagosome formation, maturation, and degradation and the regulation of autophagy by hormones, phosphoinositide 3-kinases, and mammalian target of rapamycin. It is now clear that macroautophagy in the liver is important for the balance of energy and nutrients for basic cell functions, the removal of misfolded proteins resulting from genetic mutations or pathophysiological stimulations, and the turnover of major subcellular organelles such as mitochondria, endoplasmic reticulum, and peroxisomes under both normal and pathophysiological conditions. Disturbance of autophagy function in the liver could thus have a major impact on liver physiology and liver disease. (HEPATOLOGY 2008;47: 1773-1785.)

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Autophagic degradation of peroxisomes in isolated rat hepatocytes

Cited by 65 publications

References 33 publications

Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha

Isolation and characterization of mutants impaired in the selective degradation of peroxisomes in the yeast Hansenula polymorpha

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Autophagy in the liver

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