Salicylic Acid Induces Mitochondrial Injury by Inhibiting Ferrochelatase Heme Biosynthesis Activity

Gupta, Vipul; Liu, Shujie; Ando, Hideki; Ishii, Ryohei; Tateno, Shumpei; Kaneko, Yuki; Yugami, Masato; Sakamoto, Satoshi; Yamaguchi, Yuki; Nureki, Osamu; Handa, Hiroshi

doi:10.1124/mol.113.087940

Cited by 34 publications

(28 citation statements)

References 49 publications

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“…F Phosphorylation of eIF2a at Ser51 and protein levels of Hsp90 were measured by immunoblot after knocking down FECH in HRECs. There are also prospects for novel FECH inhibitors as therapy: We have developed cremastranone analogs that may also act through FECH (Basavarajappa et al, 2015), and recently, the drugs vemurafenib (Savitski et al, 2014) and salicylic acid (Gupta et al, 2013), as well as a lipid-derived probe compound (Niphakis et al, 2015), were all shown to bind to FECH, suggesting that this protein has many potential binding clefts and is therefore likely druggable with novel compounds. FECH is the only known enzyme in humans to synthesize heme, and any loss of activity of this enzyme might result in intracellular heme deficiency (Dailey et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Ferrochelatase is a therapeutic target for ocular neovascularization

et al. 2017

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Ocular neovascularization underlies major blinding eye diseases such as “wet” age‐related macular degeneration (AMD). Despite the successes of treatments targeting the vascular endothelial growth factor (VEGF) pathway, resistant and refractory patient populations necessitate discovery of new therapeutic targets. Using a forward chemical genetic approach, we identified the heme synthesis enzyme ferrochelatase (FECH) as necessary for angiogenesis in vitro and in vivo. FECH is overexpressed in wet AMD eyes and murine choroidal neovascularization; siRNA knockdown of Fech or partial loss of enzymatic function in the Fech m1Pas mouse model reduces choroidal neovascularization. FECH depletion modulates endothelial nitric oxide synthase function and VEGF receptor 2 levels. FECH is inhibited by the oral antifungal drug griseofulvin, and this compound ameliorates choroidal neovascularization in mice when delivered intravitreally or orally. Thus, FECH inhibition could be used therapeutically to block ocular neovascularization.

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Section: Discussionmentioning

confidence: 99%

Ferrochelatase is a therapeutic target for ocular neovascularization

et al. 2017

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“…Aspirin is currently being used as a preventive medication for colorectal cancer, though the mechanism is not fully understood. Recently, it was shown that the mechanism of action of aspirin and particularly salicylic acid as an anti‐mitochondrial and anti‐inflammatory agent requires the presence of wild type FECH . Moreover, FECH mRNA expression was shown to be down‐regulated in brain glioma tissues .…”

Section: Discussionmentioning

confidence: 99%

Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer

et al. 2017

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Erythropoietic protoporphyria (EPP) is a rare cutaneous and systemic disease caused by mutations in the ferrochelatase gene (FECH). The molecular underpinnings of EPP in Middle Eastern populations and relative to other ethnic groups secondary to increased consanguinity are unknown. To understand the molecular pathogenesis of Middle Eastern EPP, we surveyed clinicopathological and molecular features in 6 large consanguineous families from Lebanon and Syria presenting with cutaneous and systemic features consistent with EPP. We observed 30% increased liver disease and 20% elevated end-stage liver complications in our EPP cohort compared to EPP patients previously reported elsewhere. In addition, Middle Eastern EPP patients in our cohort exhibited uniquely an increased incidence of colon cancer. Sequence analysis revealed 2 novel non-synonymous FECH mutations in the studied families designated p.M294T and p.I230M. In addition, FECH activity was significantly decreased (6%) in fibroblasts obtained from sun-exposed sites in a patient with p.M294T mutation, whereas in sharp contrast, protected sites from the same patient exhibited 54% activity for the gene. We also found that sun-exposed fibroblasts, relative to sun-protected and control fibroblasts, exhibited suppressed growth and atypical morphology in vitro, and that these effects were alleviated when the cells were co-cultured with sun-protected fibroblasts. Our findings on the increased incidence of colon cancer in EPP patients prompted us to survey FECH expression patterns in cancer. Using publicly available microarray datasets we found that FECH mRNA was largely significantly decreased in colon adenocarcinomas relative to normal colon tissues. Our findings suggest that families with autosomal recessive EPP should be screened more extensively for systemic involvement including liver diseases and colon cancer, and point to a previously unknown yet plausible tumor suppressor role for FECH in colon malignancy.

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“…1). Metformin and aspirin are toxic at high doses, and results with the combination could reflect convergence on a common mechanism such as mitochondrial function (see El Mir et al 2000;Gupta et al 2013). The fact that metformin largely masked the impacts of aspirin suggests that a lower dose of metformin might obtain greater benefits.…”

Section: Discussionmentioning

confidence: 99%

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

Hans

Lone

Aksenov

et al. 2015

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We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138 % of controls) for metformin, and 194 days (143 % of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120 % of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234 % of controls (i.e., health span). Metformin strongly reduced growth rates of both genders (<60 % of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (>140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of Beat more, live longer.^In contrast, metformin-treated females were only~67 % of the mass of controls. Our results suggest that hormetic agents like metformin may derive significant trade-offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways.

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Salicylic Acid Induces Mitochondrial Injury by Inhibiting Ferrochelatase Heme Biosynthesis Activity

Cited by 34 publications

References 49 publications

Ferrochelatase is a therapeutic target for ocular neovascularization

Ferrochelatase is a therapeutic target for ocular neovascularization

Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

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