Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Chen, Yingfei; Wu, Leshuang; Li, Jun; Ma, Li; Zhang, Wenli

doi:10.1096/fj.202201855rr

Cited by 12 publications

(7 citation statements)

References 111 publications

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“…ELAM increasing sensitivity to ADP through an effect on redox sensitive PTMs as a mechanism of action would explain why ELAM effectively increases ADP sensitivity in aging and the Sod1 −/− mouse but does not affect young mitochondria [ 4 ]. There are many potential post-translation modifications of the ANT protein which were recently extensively reviewed [ 34 ]. ANT can be modified by methylation, nitrosylation and nitroalkylation, acetylation, glutathionylation, phosphorylation, carbonylation, and hydroxynonenal-induced modifications.…”

Section: Discussionmentioning

confidence: 99%

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

et al. 2023

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Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. Graphical abstract ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H+ (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2 (flavin adenine dinucleotide), O2 (oxygen), ELAM (elamipretide), –SH (free thiol), –SSG (glutathionylated protein)

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Section: Discussionmentioning

confidence: 99%

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

et al. 2023

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“…A comparison of the experimental data and computed results showed the trend in the dependence between the IC 50 value and the binding energy value for ANT1 [ 35 ]. ANT1 serves as a cardiac- and skeletal-muscle-specific ATP transporter involved in mitochondrial DNA maintenance and apoptosis; in cancer cells, its overexpression can sensitize to chemotherapeutic drugs and induce apoptosis [ 58 ]. In normal cells, ANT1 is an important component in antioxidative cell-protective processes.…”

Section: Discussionmentioning

confidence: 99%

Possible Participation of Adenine Nucleotide Translocase ANT1 in the Cytotoxic Action of Progestins, Glucocorticoids, and Diclofenac on Tumor Cells

Ulchenko,

Miloykovich,

Zemlyanaya

et al. 2023

Pharmaceutics

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A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC50 was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC50 values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC50 of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action.

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“…A subset of proteins-391 out of 8,268-exhibited remarkably high variability, operationally defined as two standard deviations above the average coefficient of variation (CV, mean = 1.2 x 10 -2 ; SD = 8.6 x 10 -3 ) (Figure S5A and Table S1). These highly variable proteins were significantly enriched in pathways associated with Serotonergic synapse (including CYP2D10, GNG4, CASP3, CYP2D3, GNG8, CYP2D1, PLCB2, CYP2D26), oxidative phosphorylation (including NDUFA8, NDUFAB1, COX17, ATP5PO, CYCT, ATP6V0C, ATP5F1E, COX6B1) , and inflammatory mediator regulation of TRP channels (such as PRKCH, MAP1, ASIC2, PLCB2, KNG1 ), (Figure S5B and Table S2E) [42][43][44][45] .…”

Section: Genetic Variation In Sequences and Expression Levelsmentioning

confidence: 99%

Genetic Modulation of Protein Expression in Rat Brain

Li,

Wu,

Guarracino

et al. 2024

Preprint

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Genetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits. However, the fundamental genetic architecture and variation of protein expression have received comparatively less attention than either mRNA or classical phenotypes. In this study, we systematically quantified proteins in the brains of a large family of rats using tandem mass tag (TMT)-based quantitative mass-spectrometry (MS) technology. We identified and quantified a comprehensive proteome of 8,119 proteins from Spontaneously Hypertensive (SHR/Olalpcv), Brown Norway with polydactyly-luxate (BN-Lx/Cub), and 29 of their fully inbred HXB/BXH progeny. Differential expression (DE) analysis identified 597 proteins with significant differences in expression between the parental strains (fold change > 2 and FDR < 0.01). We characterized 95 variant peptides by proteogenomics approach and discovered 464 proteins linked to strongcis-acting quantitative trait loci (pQTLs, FDR < 0.05). We also explored the linkage of pQTLs with behavioral phenotypes in rats and examined the sex-specific pQTLs to reveal both distinct and sharedcis-pQTLs between sexes. Furthermore, by creating a novel view of the rat pangenome, we improved the ability to pinpoint candidate genes underlying pQTL. Finally, we explored the connection between the pQTLs in rat and human disorders, underscoring the translational potential of our findings. Collectively, this work demonstrates the value of large and systematic proteo-genetic datasets in understanding protein modulation in the brain and its functional linkage to complex central nervous system (CNS) traits.

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Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Cited by 12 publications

References 111 publications

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

Possible Participation of Adenine Nucleotide Translocase ANT1 in the Cytotoxic Action of Progestins, Glucocorticoids, and Diclofenac on Tumor Cells

Genetic Modulation of Protein Expression in Rat Brain

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