2000
DOI: 10.1128/mcb.20.19.7311-7318.2000
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Abstract: Leakage of mitochondrial oxidants contributes to a variety of harmful conditions ranging from neurodegenerative diseases to cellular senescence. We describe here, however, a physiological and heretofore unrecognized role for mitochondrial oxidant release. Mitochondrial metabolism of pyruvate is demonstrated to activate the c-Jun N-terminal kinase (JNK). This metabolite-induced rise in cytosolic JNK1 activity is shown to be triggered by increased release of mitochondrial H 2 O 2 . We further demonstrate that in… Show more

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Cited by 355 publications
(235 citation statements)
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References 43 publications
(50 reference statements)
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“…Activation of macrophage-mediated angiogenesis by lactate may also facilitate metastasis (Jensen et al, 1986;Zabel et al, 1996;Murray and Wilson, 2001). Moreover, low pH protects mitochondria from oxidative stress and may account for increased resistance of cancer cells to hypoxia-induced apoptosis (Bronk and Gores, 1991;Nemoto et al, 2000); (ii) increased LDH production by cancer cells can be a direct marker of intratumoral hypoxia (Firth et al, 1995), and therefore a strong marker of tumour resistance to radiotherapy and some chemotherapeutic agents; (iii) as LDH-5 is transcriptionally regulated by HIFas, high LDH serum levels may reflect an upregulated HIF-molecular cascade (Firth et al, 1995;Semenza et al, 1996;Ebert and Bunn, 1998). Hypoxia inducible factor stabilisation that occurs due to hypoxia or genetic mutations results in the overexpression of a variety of proteins linked to angiogenesis/metastasis, glycolysis and resistance to apoptosis (Semenza, 1998;Akakura et al, 2001;Harris, 2002).…”
Section: Discussionmentioning
confidence: 99%
“…Activation of macrophage-mediated angiogenesis by lactate may also facilitate metastasis (Jensen et al, 1986;Zabel et al, 1996;Murray and Wilson, 2001). Moreover, low pH protects mitochondria from oxidative stress and may account for increased resistance of cancer cells to hypoxia-induced apoptosis (Bronk and Gores, 1991;Nemoto et al, 2000); (ii) increased LDH production by cancer cells can be a direct marker of intratumoral hypoxia (Firth et al, 1995), and therefore a strong marker of tumour resistance to radiotherapy and some chemotherapeutic agents; (iii) as LDH-5 is transcriptionally regulated by HIFas, high LDH serum levels may reflect an upregulated HIF-molecular cascade (Firth et al, 1995;Semenza et al, 1996;Ebert and Bunn, 1998). Hypoxia inducible factor stabilisation that occurs due to hypoxia or genetic mutations results in the overexpression of a variety of proteins linked to angiogenesis/metastasis, glycolysis and resistance to apoptosis (Semenza, 1998;Akakura et al, 2001;Harris, 2002).…”
Section: Discussionmentioning
confidence: 99%
“…Our results are consistent with a previous study (Luo et al, 1997), which showed that ERK1 and ERK2 were induced in phechromocytoma PC12 cells treated with FCCP, a mitochondria-specific ionophore, which also caused an increase in steady state [Ca 2+ ]. Additionally, increased mitochondrial H 2 O 2 , possibly representing mitochondrial stress, also induced MAP kinases in Hela cells (Nemoto et al, 2000).…”
Section: Discussionmentioning
confidence: 99%
“…They are important components of cellular signaling (e.g., Nemoto et al. 2000) and immune function (Babior et al. 1973; Forman and Torres 2002), but in excess can cause DNA, lipid, and protein damage and disrupt cellular function (Harman 1956; Beckman and Ames 1998; Buffenstein et al.…”
Section: Introductionmentioning
confidence: 99%