Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Shetty, Trupti; Sishtla, Kamakshi; Park, Bomina; Repass, Matthew J.; Corson, Timothy W.

doi:10.1101/836304

Cited by 3 publications

(2 citation statements)

References 57 publications

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“…In addition, endothelial specific PHGDH deletion led to vascular defects with decreased glutathione and NADPH synthesis in vivo (69), suggesting serine synthesis is essential for heme production in endothelial cells. Further, heme depletion selectively reduced the protein expression and activity of components of the mitochondrial electron transport chain, which could lead to enhanced mitochondrial dysfunction in endothelial cells (69)(70)(71). It will be interesting to ascertain the downstream interactions of hemoproteins upon FECH depletion in retinal and choroidal angiogenesis mouse models.…”

Section: Discussionmentioning

confidence: 99%

Ferrochelatase regulates retinal neovascularization

Pasha

White

Corson

2020

Preprint

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Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an anti-fungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin blocked pathological tuft formation and revascularized areas of vasoobliteration faster than vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.

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Section: Discussionmentioning

confidence: 99%

Ferrochelatase regulates retinal neovascularization

Pasha

White

Corson

2020

Preprint

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“…In humans, defects in heme synthesis result in the accumulation of its intermediates leading to porphyria [8]. In addition, previous studies have shown that heme synthesis declines with age and its deficiency leads to mitochondrial dysfunction and iron accumulation leading to oxidative stress [9,10]. On the other hand, deficiency of heme oxygenases, enzymes that are necessary for heme degradation, has been implicated in the development of several age-related disorders, such as Alzheimer's disease, cancer as well as cardiovascular and metabolic diseases [11].…”

Section: Introductionmentioning

confidence: 99%

Lifespan regulation by targeting heme signaling in yeast

Patnaik,

Nady,

Barlit

et al. 2024

Preprint

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Heme is an essential prosthetic group that serves as a co-factor and a signaling molecule. Heme levels decline with age, and its deficiency is associated with multiple hallmarks of aging, including anemia, mitochondrial dysfunction, and oxidative stress. Dysregulation of heme homeostasis has been also implicated in aging in model organisms suggesting that heme may play an evolutionarily conserved role in controlling lifespan. However, the underlying mechanisms and whether heme homeostasis can be targeted to promote healthy aging remain unclear. Here we used Saccharomyces cerevisiae as a model to investigate the role of heme in aging. For this, we have engineered a heme auxotrophic yeast strain expressing a plasma membrane-bound heme permease from Caenorhabditis elegans (ceHRG-4). This system can be used to control intracellular heme levels independently of the biosynthetic enzymes by manipulating heme concentration in the media. We observed that heme supplementation leads to significant lifespan extension in yeast. Our findings revealed that the effect of heme on lifespan is independent of the Hap4 transcription factor. Surprisingly, heme-supplemented cells had impaired growth on YPG medium, which requires mitochondrial respiration to be used, suggesting that these cells are respiratory deficient. Together, our results demonstrate that heme homeostasis is fundamentally important for aging biology and manipulating heme levels can be used as a promising therapeutic target for promoting longevity.

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The mitochondrial carrier SFXN1 is critical for Complex III integrity and cellular metabolism

Acoba

Alpergin

Renuse

et al. 2020

Preprint

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19 20 Mitochondrial carriers (MC) mediate the passage of small molecules across the inner 21 mitochondrial membrane (IMM) enabling regulated crosstalk between compartmentalized 22 reactions. Despite MCs representing the largest family of solute carriers in mammals, most have 23 not been subjected to a comprehensive investigation, limiting our understanding of their 24 metabolic contributions. Here, we functionally characterized SFXN1, a member of the non-25 canonical, sideroflexin MC family. We find that SFXN1, an integral membrane protein in the IMM 26 with an uneven number of transmembrane domains, is a novel TIM22 substrate. SFXN1 27 deficiency specifically impairs Complex III (CIII) biogenesis, activity, and assembly, 28 compromising coenzyme Q levels. This CIII dysfunction is independent of one-carbon 29 metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, 30 SFXN1 supports CIII function by participating in heme and central carbon metabolism. Our 31 findings highlight the multiple ways that SFXN1-based amino acid transport impacts 32 mitochondrial and cellular metabolic efficiency. 33 34 Keywords: mitochondria, mitochondrial carrier, sideroflexin, SFXN1, Complex III, OXPHOS, 35 amino acid, serine, heme, metabolism 36 explained by a defective 1C metabolism, which represents the only well-documented 99 physiological role for SFXN1 (Kory et al., 2018). Instead, we show that SFXN1 is important for 100 heme and central carbon metabolism, both of which support CIII function to varying extents. 101Collectively, these data define additional roles and thus provide a richer context for how SFXN1-102 mediated amino acid transport maintains mitochondrial integrity and promotes metabolic 103 plasticity. 104 RESULTS 105

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Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Cited by 3 publications

References 57 publications

Ferrochelatase regulates retinal neovascularization

Ferrochelatase regulates retinal neovascularization

Lifespan regulation by targeting heme signaling in yeast

The mitochondrial carrier SFXN1 is critical for Complex III integrity and cellular metabolism

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