Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

Yien, Yvette Y.; Perfetto, Mark

doi:10.3389/fcell.2022.895521

Cited by 18 publications

(13 citation statements)

References 156 publications

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“…By contrast, the transcript levels of ALAS1, PPO, and FECH, were not significantly changed following ONC201 or TR-57 treatment, suggesting that loss of these proteins is due to degradation caused by ClpP activation (Figure 6A). Immunoblot analysis validated ONC201 and TR-57 mediated ALAS1 decline in WT, but not in ClpP KO SUM159 cells (Figure 6B), consistent with previous reports of ClpP degrading ALAS1 (Kubota et al, 2016;Wong and Houry, 2019;Yien and Perfetto, 2022). The downregulation of ALAS1 occurred as early as 30 min of treatment with TR-57 in WT, but not knockout SUM159 cells (Figure 6D).…”

Section: Clpp Activation Induces Atf4 Expression and Affects Atf4depe...supporting

confidence: 90%

“…Since LonP, another mitochondrial matrix protease, has also been reported to degrade ALAS1 (Tian et al, 2011;Kubota et al, 2016;Yien and Perfetto, 2022), we investigated whether the loss of ALAS1 was due to ClpP or LonP activation. To accomplish this, bortezomib (10 nM) was used to inhibit both LonP and the proteasome, whereas epoxomicin (1 μM) was used as an inhibitor of only the proteasome (Lu et al, 2013;Csizmadia et al, 2016;Lee et al, 2022).…”

Section: Clpp Activation Induces Atf4 Expression and Affects Atf4depe...mentioning

confidence: 99%

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Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

et al. 2023

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ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

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Section: Clpp Activation Induces Atf4 Expression and Affects Atf4depe...supporting

confidence: 90%

Section: Clpp Activation Induces Atf4 Expression and Affects Atf4depe...mentioning

confidence: 99%

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

et al. 2023

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“…Heme-bound proteins act as heme-responsive sensors and regulate transcription [20–24], microRNA splicing and processing [25], translation [26], heme degradation [27], protein degradation [28, 29], K + channel function [30], redox status [30–32] and protein-protein interactions [20]. The enzyme-catalyzed chelation of Fe 2+ in PPIX corresponds to the terminal step of the heme biosynthetic pathway [33–35]. This reaction is finely regulated as both PPIX and iron ion are potentially cytotoxic [36, 37].…”

Section: Introductionmentioning

confidence: 99%

Uncovering porphyrin accumulation in the tumor microenvironment

Adapa,

Sami,

Meshram

et al. 2024

Preprint

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Heme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be exquisitely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termedPorphyrin Overdrive. Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TME's stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no porphyrin accumulation, and CAFs deprived of tumor cease porphyrin overproduction, indicating that both cancer and tumor-stromal porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.

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“…Heme is a vital cofactor for diverse redox processes such as oxygen transport, mitochondrial respiration, and detoxification 3 . Heme synthesis is highly compartmentalized between mitochondria and the cytosol and multiple steps of the eight enzymatic reactions require the shuttling of substrates across the IMM 4 . The first step involves the uptake of glycine into the mitochondrial matrix via SLC25A38 5,6 , where glycine is condensed with succinyl-CoA to produce 5-aminolevulinate (5-ALA).…”

Section: Introductionmentioning

confidence: 99%

The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38

Tan,

Dengler,

Darawsheh

et al. 2024

Preprint

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Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane to ensure adequate amounts of substrates and cofactors to support the redox and biosynthetic reactions in the mitochondrial matrix. However, how the abundance of mitochondrial transporters is regulated and the mechanisms controlling mitochondrial metabolite concentrations remain poorly defined. Using protein half-life data and mRNA-protein correlation analysis, we identify SLC25A38, a mitochondrial glycine transporter, as a short-lived protein, whose mitochondrial pool is turned over with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of different cellular proteolytic systems revealed that proteasomal and lysosomal systems do not affect the stability of SLC25A38. Instead, we found that the mitochondrial iAAA-protease YME1L1 regulates the abundance and turnover of SLC25A38 under steady-state conditions. Identification of YME1L1 as the molecular player that regulates SLC25A38 levels will open up avenues to explore how cells coordinate mitochondrial substrate uptake with heme synthesis and other glycine-dependent mitochondrial metabolic pathways under physiological state or in response to environmental cues.

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Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

Cited by 18 publications

References 156 publications

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer

Uncovering porphyrin accumulation in the tumor microenvironment

The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38

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