Cardiolipin and its metabolites move from mitochondria to other cellular membranes during death receptor-mediated apoptosis

Sorice, Maurizio; Circella, A.; Cristea, Ileana M.; Garofalo, Tina; Renzo, Livia Di; Alessandri, Cristiano; Valesini, Guido; Esposti, Mauro Degli

doi:10.1038/sj.cdd.4401457

Cited by 130 publications

(141 citation statements)

References 64 publications

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“…Two different mechanisms are believed to be used by the cell to ensure mitochondrial homeostasis and survival; apoptosis and mitophagy but, to the best of our knowledge, none of these has been considered in the context of thermal acclimation. Of interest, both processes are potently regulated by cardiolipin and its function to anchor cytochrome c to the inner mitochondrial membrane, and have been shown to be triggered by cardiolipin modifications (Bradley et al, 2016;Chu et al, 2013;Sorice et al, 2004). The release of cytochrome c triggers apoptosis and cell death (Goldstein et al, 2000), and it is therefore possible that the increased cytochrome c effect we observed upon warming induced this mechanism.…”

Section: Discussionmentioning

confidence: 87%

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Pichaud

Ekström

Hellgren

et al. 2017

Journal of Experimental Biology

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Although the mitochondrial metabolism responses to warm acclimation have been widely studied in fish, the time course of this process is less understood. Here, we characterized the changes of rainbow trout (Oncorhynchus mykiss) cardiac mitochondrial metabolism during acute warming from 10 to 16°C, and during the subsequent warm acclimation for 39 days. We repeatedly measured mitochondrial oxygen consumption in cardiac permeabilized fibers and the functional integrity of mitochondria (i.e. mitochondrial coupling and cytochrome c effect) at two assay temperatures (10 and 16°C), as well as the activities of citrate synthase (CS) and lactate dehydrogenase (LDH) at room temperature. LDH and CS activities significantly increased between day 0 (10°C acclimated fish) and day 1 (acute warming to 16°C) while mitochondrial oxygen consumption measured at respective in vivo temperatures did not change. Enzymatic activities and mitochondrial oxygen consumption rates significantly decreased by day 2, and remained stable during warm acclimation (days 2-39). The decrease in rates of oxygen between day 0 and day 1 coincided with an increased cytochrome c effect and a decreased mitochondrial coupling, suggesting a structural/ functional impairment of mitochondria during acute warming. We suggest that after 2 days of warm acclimation, a new homeostasis is reached, which may involve the removal of dysfunctional mitochondria. Interestingly, from day 2 onwards, there was a lack of differences in mitochondrial oxygen consumption rates between the assay temperatures, suggesting that warm acclimation reduces the acute thermal sensitivity of mitochondria. This study provides significant knowledge on the thermal sensitivity of cardiac mitochondria that is essential to delineate the contribution of cellular processes to warm acclimation.

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Section: Discussionmentioning

confidence: 87%

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Pichaud

Ekström

Hellgren

et al. 2017

Journal of Experimental Biology

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“…A few PE (three lipids), PI (three lipids), PS (two lipids), and a PA (one lipid) were also observed. Acyl-PG are unusual lipids commonly found in bacterial cells, which have been reported to accumulate in mitochrondrial fractions of mammalian apoptotic cells (31), and to be present at significant levels in Golgi membranes (32). PG lipids are present at low levels (1-2%) in most animal tissue and can serve as the precursor of CL found in mitochrondrial membranes.…”

Section: Resultsmentioning

confidence: 99%

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Eberlin

Gabay

Fan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

103

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Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas.biostatistics | transgenic models | lipidomics | metabolomics | cancer T he v-myc avian myelocytomatosis viral oncogene homolog (MYC) is commonly overexpressed in human neoplasia (1, 2) and has been strongly associated with the clinical aggressiveness of human cancers (3, 4). MYC is particularly associated with the pathogenesis of hematopoietic tumors such as lymphomas and of epithelial tumors (5, 6). In Burkitt's lymphoma, for example, the c-Myc gene is translocated to one of the Ig loci in virtually all tumors (5,7,8). The MYC oncogene contributes to tumorigenesis by functioning as a global regulator of transcription involving many cellular programs, including cellular growth, metabolism, and lipid synthesis (9, 10). MYC induces a global shift in metabolism associated with anaerobic glycolysis, a phenomenon known as the Warburg effect (11). Several studies have shown a relationship between MYC regulation and metabolism in lymphomas, especially as related to the processes of glycolysis and glutaminolysis (12, 13). Some reports suggest that MYC regulates fatty acid synthesis, specifically palmitate (14); however, little is known about the relationship between MYC expression and the up-regulation or down-regulation of various lipid species in lymphomas.We have generated transgenic mice to conditionally regulate expression of MYC oncogenes alone or in combination with oncogenes such as rat sarcoma (RAS), BCR-ABL, and BCL2 to produce many transgenic models of cancers, including T-cell acute lymphocytic leukemia, acute myeloid leukemia, osteosarcoma, lung adenocarc...

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“…Lipid extraction from purified mitochondria was accomplished as described earlier and extracts were analyzed by nanoelectrospray time of flight mass spectrometry using an LCT instrument (Micromass, Elstree, UK) set in positive ion mode. 33 A few microliters of the extracts were injected using capillary voltage at 2250 V and sample cone at 35 V. Semi-quantitative evaluation of lipid peaks was undertaken using a set of internal reference ions that maintained equivalent relationships within multiple spectra of the same sample and showed little variation between WT and HtrA2 KO samples. The data were normalized to the major phosphatidyl choline, that is PO-PC (mass-tocharge ratio m/z 758), which was in turn normalized to other reference ions such as C-24 ceramide (m/z 685).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

et al. 2008

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Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.

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Cardiolipin and its metabolites move from mitochondria to other cellular membranes during death receptor-mediated apoptosis

Cited by 130 publications

References 64 publications

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

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