ORCID Profile
0000-0003-4189-9422
Current Organisations
Peter MacCallum Cancer Centre
,
University of Melbourne
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Biochemistry and Cell Biology | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Cell Metabolism | Developmental Genetics (incl. Sex Determination) | Gene Expression (incl. Microarray and other genome-wide approaches)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: eLife Sciences Publications, Ltd
Date: 21-09-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540936
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.BCP.2008.08.021
Abstract: Thioredoxin reductase (TrxR) is a key selenoprotein antioxidant enzyme and a potential target for anti-cancer drugs. One potent inhibitor of TrxR is the gold (I) compound auranofin, which can trigger mitochondrial-dependent apoptosis pathways. The exact mechanism of apoptosis induction by auranofin is not yet clear, but there are indications that mitochondrial oxidative stress is a central event. We assessed the redox state of the peroxiredoxins (Prxs) in Jurkat T-lymphoma cells treated with auranofin, and found that mitochondrial Prx3 was considerably more sensitive to oxidation than the cytosolic Prx1 and 2, indicating selective mitochondrial stress. Prx3 oxidation was detected at apoptotic doses of auranofin in several cell types, and occurred before other mitochondrial events including cytochrome c release and mitochondrial depolarisation. Auranofin was also able to sensitise U937 cells to TNF-alpha-mediated apoptosis. Auranofin-induced apoptosis was effectively blocked by the overexpression of Bcl-2, and Bax/Bak deficient mouse embryonic fibroblasts were also resistant to apoptosis, indicating a central role for the pro-apoptotic proteins of this family in auranofin-triggered apoptosis. Auranofin exposure inhibited the proliferation of apoptosis-resistant cells, and at higher doses of auranofin could cause cell death through necrosis. We conclude that auranofin induces apoptosis in cells through a Bax/Bak-dependent mechanism associated with selective disruption of mitochondrial redox homeostasis in conjunction with oxidation of Prx3.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540933
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540939
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540948.V1
Abstract: Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: eLife Sciences Publications, Ltd
Date: 16-06-2016
DOI: 10.7554/ELIFE.10575
Abstract: Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to erse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mitochondrial DNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis.
Publisher: eLife Sciences Publications, Ltd
Date: 30-04-2019
DOI: 10.7554/ELIFE.42881
Abstract: Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. The Hippo pathway and effectors Yap and Taz control organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that YAP displays dynamic changes in lymphatic progenitors and Yap1 is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear YAP in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage.
Publisher: Portland Press Ltd.
Date: 23-12-2009
DOI: 10.1042/BJ20091541
Abstract: Prxs (peroxiredoxins) are a family of proteins that are extremely effective at scavenging peroxides. The Prxs exhibit a number of intriguing properties that distinguish them from conventional antioxidants, including a susceptibility to inactivation by hyperoxidation in the presence of excess peroxide and the ability to form complex oligomeric structures. These properties, combined with a high cellular abundance and reactivity with hydrogen peroxide, have led to speculation that the Prxs function as redox sensors that transmit signals as part of the cellular response to oxidative stress. Multicellular organisms express several different Prxs that can be categorized by their subcellular distribution. In mammals, Prx 3 and Prx 5 are targeted to the mitochondrial matrix. Mitochondria are a major source of hydrogen peroxide, and this oxidant is implicated in the damage associated with aging and a number of pathologies. Hydrogen peroxide can also act as a second messenger, and is linked with signalling events in mitochondria, including the induction of apoptosis. A simple kinetic competition analysis estimates that Prx 3 will be the target for up to 90% of hydrogen peroxide generated in the matrix. Therefore, mitochondrial Prxs have the potential to play a major role in mitochondrial redox signalling, but the extent of this role and the mechanisms involved are currently unclear.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540930
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540939.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 05-1995
DOI: 10.1016/S0968-0004(00)89007-6
Abstract: The discovery of structural and functional similarities between the product of the nematode cell-death gene ced-3 and mammalian interleukin-1 beta-converting enzyme (ICE) is providing important insights into the molecular mechanism of apoptosis. This article summarizes the current knowledge of ICE and its homologues, and how these may be involved in regulating apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2021
DOI: 10.1038/S41467-021-23240-7
Abstract: Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese ( db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
Publisher: Portland Press Ltd.
Date: 12-11-2010
DOI: 10.1042/BJ20101156
Abstract: Prxs (peroxiredoxins) are a ubiquitous family of cysteine-dependent peroxidases that react rapidly with H2O2 and alkyl hydroperoxides and provide defence against these reactive oxidants. Hydroperoxides are also formed on amino acids and proteins during oxidative stress, and they too are a potential cause of biological damage. We have investigated whether Prxs react with amino acid, peptide and protein hydroperoxides, and whether the reactions are sufficiently rapid for these enzymes to provide antioxidant protection against these oxidants. Isolated Prx2, which is a cytosolic protein, and Prx3, which resides within mitochondria, were reacted with a selection of hydroperoxides generated by γ-radiolysis or singlet oxygen, on free amino acids, peptides and proteins. Reactions were followed by measuring the accumulation of disulfide-linked Prx dimers, via non-reducing SDS/PAGE, or the loss of the corresponding hydroperoxide, using quench-flow and LC (liquid chromatography)/MS. All the hydroperoxides induced rapid oxidation, with little difference in reactivity between Prx2 and Prx3. N-acetyl leucine hydroperoxides reacted with Prx2 with a rate constant of 4×104 M−1·s−1. Hydroperoxides present on leucine, isoleucine or tyrosine reacted at a comparable rate, whereas histidine hydroperoxides were ~10-fold less reactive. Hydroperoxides present on lysozyme and BSA reacted with rate constants of ~100 M−1·s−1. Addition of an uncharged derivative of leucine hydroperoxide to intact erythrocytes caused Prx2 oxidation with no concomitant loss in GSH, as did BSA hydroperoxide when added to concentrated erythrocyte lysate. Prxs are therefore favoured intracellular targets for peptide rotein hydroperoxides and have the potential to detoxify these species in vivo.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2016
DOI: 10.1038/NCB3389
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540921.V1
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Portland Press Ltd.
Date: 30-01-2019
DOI: 10.1042/BST20180335
Abstract: Zebrafish (Danio rerio) are becoming an increasingly powerful model organism to study the role of metabolism in disease. Since its inception, the zebrafish model has relied on unique attributes such as the transparency of embryos, high fecundity and conservation with higher vertebrates, to perform phenotype-driven chemical and genetic screens. In this review, we describe how zebrafish have been used to reveal novel mechanisms by which metabolism regulates embryonic development, obesity, fatty liver disease and cancer. In addition, we will highlight how new approaches in advanced microscopy, transcriptomics and metabolomics using zebrafish as a model system have yielded fundamental insights into the mechanistic underpinnings of disease.
Publisher: Proceedings of the National Academy of Sciences
Date: 09-2016
Abstract: Dietary selenium and selenoproteins play important roles in regulating redox processes that impact human health. The human genome includes 25 genes for selenoproteins, which have erse roles in redox homeostasis, thyroid hormone metabolism, endoplasmic reticulum quality control, selenium transport, and other functions. Selenoprotein H ( seph ) is a recently identified nucleolar oxidoreductase with DNA-binding properties whose function is not well understood. In this work, we used a unique combination of unbiased metabolomic and transcriptomic approaches in zebrafish to discover that seph is an essential regulator of redox homeostasis that regulates p53. In addition, we demonstrate the seph -deficient adults are prone to chemically induced carcinogenesis. Our results suggest that seph suppresses oxidative stress and DNA damage in the nucleolus.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540945
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540948
Abstract: Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.LEUKRES.2009.01.001
Abstract: Soluble CD83 (sCD83), a potent immunosuppressive agent, circulates at elevated levels in some chronic lymphocytic leukemia (CLL) patients. We report that CLL patients with elevated plasma sCD83 levels had significantly shorter (P=0.038) treatment free survival. Culture of CLL cells with solid phase CD83 mAb+IL-4 significantly increases sCD83 release (23-117-fold, P=0.013) and ligation of normal donor PBMC with solid phase CD83 mAb alone induces similar significant increases in sCD83 release (P=0.003). RT-PCR analysis detected the presence of a transcript for sCD83 in 2/3 CLL s les. These results suggest sCD83 release may play a regulatory role in CLL progression.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549508
Abstract: Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked i in vitro /i and i in vivo /i synergy with venetoclax and overcomes venetoclax resistance in primary patient s les. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. i This article is highlighted in the In This Issue feature, p. 587 /i /
Publisher: Elsevier BV
Date: 05-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540942
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540915.V1
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Proceedings of the National Academy of Sciences
Date: 22-05-2023
Abstract: The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1–NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540936.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/2159-8290.CD-21-0522
Abstract: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587
Publisher: Elsevier BV
Date: 06-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540927.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540918
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540915
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540933.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: EMBO
Date: 22-10-2018
Publisher: American Chemical Society (ACS)
Date: 24-08-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540918.V1
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540942.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Springer Science and Business Media LLC
Date: 02-2014
DOI: 10.1038/506299A
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540924
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540930.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540924.V1
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Cold Spring Harbor Laboratory
Date: 26-07-2023
DOI: 10.1101/2023.07.24.550437
Abstract: The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. Following this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma with an in idual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540927
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.BBRC.2008.07.133
Abstract: Bcl-2 is reported to augment the antioxidant capacity of cells and this is hypothesized to contribute to the anti-apoptotic activity of this oncoprotein. We generated a number of stable Jurkat cell lines expressing varying levels of Bcl-2, and showed a strong correlation between Bcl-2 levels and resistance to Fas-mediated apoptosis. While in idual differences could be detected, there was no overall correlation between Bcl-2 and the expression and activity of superoxide dismutases, catalase, glutathione peroxidases, thioredoxin, thioredoxin reductases, and peroxiredoxins. Cells transfected with Bcl-2 averaged 70% more glutathione than parental cells, but there was no correlation between glutathione and resistance to apoptosis. This challenges the hypothesis that the anti-apoptotic properties of Bcl-2 are linked to a global increase in antioxidant status.
Publisher: Oxford University Press (OUP)
Date: 02-02-2007
Abstract: The anti-apoptotic oncogene bcl-2 is hypothesized to increase the antioxidant status of cells, thereby protecting them from oxidative stress. In this study, we examined hydrogen peroxide (H2O2)-mediated oxidative stress in Jurkat T lymphoma cells. Over-expression of Bcl-2 did not inhibit cytotoxicity at doses of H2O2 that caused necrosis (>200 microM), but it did block cell death at apoptotic doses (<200 microM). However, these cells exhibited the same initial level of protein and lipid oxidation following exposure to H2O2 as the parental cells, indicating that the anti-apoptotic activity is not associated with general antioxidant properties. Bcl-2 expression was able to protect against secondary protein carbonyl formation, which was linked to lysosome stabilization. Assessment of micronuclei formation in cells over-expressing Bcl-2 showed evidence of increased genomic instability, consistent with the impairment of apoptosis in damaged cells. We conclude that while Bcl-2 can block cytotoxicity associated with apoptosis-inducing levels of oxidative stress, it does not protect the cells from the stress itself. Bcl-2 may promote tumourigenesis by preventing the removal of oxidatively damaged cells.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540921
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Portland Press Ltd.
Date: 12-06-2009
DOI: 10.1042/BJ20090242
Abstract: The Prxs (peroxiredoxins) are a family of cysteine-dependent peroxidases that decompose hydrogen peroxide. Prxs become hyperoxidized when a sulfenic acid formed during the catalytic cycle reacts with hydrogen peroxide. In the present study, Western blot methodology was developed to quantify hyperoxidation of in idual 2-Cys Prxs in cells. It revealed that Prx 1 and 2 were hyperoxidized at lower doses of hydrogen peroxide than would be predicted from in vitro data, suggesting intracellular factors that promote hyperoxidation. In contrast, mitochondrial Prx 3 was considerably more resistant to hyperoxidation. The concentration of Prx 3 was estimated at 125 μM in the mitochondrial matrix of Jurkat T-lymphoma cells. Although the local cellular environment could influence susceptibility, purified Prx 3 was also more resistant to hyperoxidation, suggesting that despite having C-terminal motifs similar to sensitive eukaryote Prxs, other structural features must contribute to the innate resilience of Prx 3 to hyperoxidation.
Publisher: Elsevier BV
Date: 12-2012
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.DEVCEL.2022.02.004
Abstract: The coordinated regulation of growth control and metabolic pathways is required to meet the energetic and biosynthetic demands associated with proliferation. Emerging evidence suggests that the Hippo pathway effector Yes-associated protein 1 (YAP) reprograms cellular metabolism to meet the anabolic demands of growth, although the mechanisms involved are poorly understood. Here, we demonstrate that YAP co-opts the sterol regulatory element-binding protein (SREBP)-dependent lipogenic program to facilitate proliferation and tissue growth. Mechanistically, YAP stimulates de novo lipogenesis via mechanistic target of rapamcyin (mTOR) complex 1 (mTORC1) signaling and subsequent activation of SREBP. Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. We also find that the SREBP target genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) are conditionally required to support YAP-dependent proliferation and tissue growth. These studies reveal that de novo lipogenesis is a metabolic vulnerability that can be targeted to disrupt YAP-dependent proliferation and tissue growth.
Publisher: Wiley
Date: 19-02-2010
DOI: 10.1016/J.FEBSLET.2010.02.042
Abstract: Mitochondrial peroxiredoxin 3 (Prx 3) is rapidly oxidized in cells exposed to phenethyl isothiocyanate (PEITC) and auranofin (AFN), but the mechanism of oxidation is unclear. Using HL-60 cells deplete of mitochondrial DNA we show that peroxiredoxin 3 oxidation and cytotoxicity requires a functional respiratory chain. Thioredoxin reductase (TrxR) could be inhibited by up to 90% by auranofin without direct oxidation of peroxiredoxin 3. However, inhibition of thioredoxin reductase promoted peroxiredoxin 3 oxidation and cytotoxicity in combination with phenethyl isothiocyanate or antimycin A. We conclude that rapid peroxiredoxin 3 oxidation occurs as a consequence of increased oxidant production from the mitochondrial respiratory chain.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540945.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Chemical Society (ACS)
Date: 19-06-2009
DOI: 10.1021/BI900558G
Abstract: Peroxiredoxins (Prxs) are a ubiquitous family of thiol peroxidases that protect cells from peroxides and have a putative role in redox signaling. In this study, we investigated the redox properties of human Prx 3, a typical 2-Cys Prx that is localized to the mitochondrial matrix. We found that Prx 3 displayed strong reactivity with H(2)O(2), with a competitive kinetic approach generating a second order rate constant of 2 x 10(7) M(-1) s(-1). This is considerably higher than typical thiols and similar to values for other mammalian 2-Cys Prxs. In contrast, Prx 3 reacted very slowly with the thiol alkylating agents iodoacetamide and N-ethylmaleimide. Using dithiothreitol redox buffers, we measured the redox potential of Prx 3 of -290 mV. This is similar to the redox potential of mitochondrial thioredoxin 2 and is consistent with optimal operation of Prx 3 in the mitochondrial matrix.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549508.V1
Abstract: Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked i in vitro /i and i in vivo /i synergy with venetoclax and overcomes venetoclax resistance in primary patient s les. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. i This article is highlighted in the In This Issue feature, p. 587 /i /
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.FREERADBIOMED.2007.11.017
Abstract: It is hypothesized that activation of death receptors disrupts the redox homeostasis of cells and that this contributes to the induction of apoptosis. The redox status of the peroxiredoxins, which are extremely sensitive to increases in H2O2 and disruption of the thioredoxin system, were monitored in Jurkat T lymphoma cells undergoing Fas-mediated apoptosis. The only detectable change during the early stages of apoptosis was oxidation of mitochondrial peroxiredoxin 3. Increased H2O2 triggers peroxiredoxin overoxidation to a sulphinic acid however during apoptosis peroxiredoxin 3 was captured as a disulfide, suggesting impairment of the thioredoxin system responsible for maintaining peroxiredoxin 3 in its reduced form. Peroxiredoxin 3 oxidation was an early event, occurring within the same timeframe as increased mitochondrial oxidant production, caspase activation and cytochrome c release. It preceded other major apoptotic events including mitochondrial permeability transition and phosphatidylserine exposure, and glutathione depletion, global thiol protein oxidation and protein carbonylation. Peroxiredoxin 3 oxidation was also observed in U937 cells stimulated with TNF-alpha. We hypothesize that the selective oxidation of peroxiredoxin 3 leads to an increase in mitochondrial H2O2 and that this may influence the progression of apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
Publisher: American Society of Hematology
Date: 28-03-2013
DOI: 10.1182/BLOOD-2012-12-471201
Abstract: Glucose metabolism enhances hematopoietic stem cell formation and function in the vertebrate embryo Glucose metabolism modulates hif1α activity via mitochondrial generation of reactive oxygen species to impact HSC-relevant gene expression
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 2014
Start Date: 07-2019
End Date: 07-2019
Amount: $743,554.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 12-2022
Amount: $400,000.00
Funder: Australian Research Council
View Funded Activity