Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia

Abrey J Yeo, Kok L Chong, Magtouf Gatei, Dongxiu Zou, Romal Stewart, Sarah Withey, Ernst Wolvetang, Robert G Parton, Adam D Brown, Michael B Kastan, David Coman, Martin F Lavin, Abrey J Yeo, Kok L Chong, Magtouf Gatei, Dongxiu Zou, Romal Stewart, Sarah Withey, Ernst Wolvetang, Robert G Parton, Adam D Brown, Michael B Kastan, David Coman, Martin F Lavin

Abstract

There is evidence that ATM mutated in ataxia-telangiectasia (A-T) plays a key role in protecting against mitochondrial dysfunction, the mechanism for which remains unresolved. We demonstrate here that ATM-deficient cells are exquisitely sensitive to nutrient deprivation, which can be explained by defective cross talk between the endoplasmic reticulum (ER) and the mitochondrion. Tethering between these two organelles in response to stress was reduced in cells lacking ATM, and consistent with this, Ca2+ release and transfer between ER and mitochondria was reduced dramatically when compared with control cells. The impact of this on mitochondrial function was evident from an increase in oxygen consumption rates and a defect in mitophagy in ATM-deficient cells. Our findings reveal that ER-mitochondrial connectivity through IP3R1-GRP75-VDAC1, to maintain Ca2+ homeostasis, as well as an abnormality in mitochondrial fusion defective in response to nutrient stress, can account for at least part of the mitochondrial dysfunction observed in A-T cells.

Keywords: Cell Biology; Functional Aspects of Cell Biology; Organizational Aspects of Cell Biology.

Conflict of interest statement

None of the authors have a conflict of interest. This study was not funded by any commercial entity and has not attracted any intellectual property protection or patents.

© 2020 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Generation of ATM-deficient cells and hypersensitivity to glucose deprivation (A) ATM-deficient HBEC3-KT cells (B3) were generated using the CRISPR-Cas9 system. A 15-bp deletion was generated in exon 57 of the ATM gene as shown in the sequence alignment and genotyping PCR. Immunoblotting confirmed the absence of the ATM protein and kinase activity in B3 cells following exposure to H2O2. C5 was another ATM-deficient cell line generated and used as a negative control. (B) Immunoblotting using antibodies against ATM and phospho-ATM S1981 demonstrated that ATM is activated following exposure to 2DG. This was in the absence of DNA damage because neither H2AX nor KAP1 was phosphorylated. α-Tubulin was used as a loading control. No signal for ATM or phospho-ATM was observed in B3. (C) Immunostaining of cells exposed to 2DG confirms that glucose deprivation is capable of activating ATM. Green, ATM protein; red, phospho-ATM S1981; green, YH2AX as a marker for DNA damage; blue, DAPI. Scale bar, 5 μm. ∗p 

Figure 2

Defect in ER-mitochondrial interaction in…

Figure 2

Defect in ER-mitochondrial interaction in ATM-deficient cells (A) Electron microscopy of HBEC3-KT and…

Figure 2
Defect in ER-mitochondrial interaction in ATM-deficient cells (A) Electron microscopy of HBEC3-KT and B3 cells with and without exposure to 2DG. A distance of ≤25 nm between mitochondria and ER is considered as a contact site. Each contact site is highlighted in pink. An increase in the number of contact sites were observed in HBEC3-KT cells exposed to 2DG, whereas the opposite was observed for B3. (B) Quantitation of the number of contact sites between mitochondria and ER in HBEC3-KT and B3 cells in the presence or absence of 2DG performed in a blind fashion. (C and D) (C) Co-staining using an antibody against Grp75 (green) and MitoTracker (red) was performed on HBEC3-KT and B3 cells in the presence or absence of 2DG. An increase in the fluorescence intensity was observed in HBEC3-KT cells following exposure to 2DG but not in B3. These data are quantitated in (D). Scale bar, 5 μm. (E) Immunoblotting for Grp75, IPR1, and VDAC1 in cells following exposure to 2DG showed no differences in protein levels between HBEC3-KT and B3. This suggested a change in Grp75 localization in 2DG-treated HBEC3-KT cells and not an increase in protein levels. α-Tubulin was used as a loading control. (F and G) (F) Proximity ligation assay (PLA) using antibodies against IP3R1 (ER) and GRP75 (mitochondria) was performed as a means of showing increased interaction between GRP75 and IP3R1. An increase in the number of foci in HBEC3-KT cells following exposure to 2DG was observed. Quantitation of these data is shown in (G). Scale bar, 5 μm. Appropriate negative control with no primary antibody was performed. All data are plotted as a mean ± SD. n = 3, ∗p 

Figure 3

Defect in Ca 2+ transfer…

Figure 3

Defect in Ca 2+ transfer between ER and mitochondria in ATM-deficient cells in…

Figure 3
Defect in Ca2+ transfer between ER and mitochondria in ATM-deficient cells in response to glucose deprivation (A) Intracellular calcium was measured using FURA-2 as a calcium indicator. A significant increase in calcium was observed in HBEC3-KT cells treated with 2DG when compared with B3. (B) Mitochondrial calcium was measured using Rhodamine-2AM. Similar to results observed with FURA-2, a significant increase in calcium was seen in HBEC3-KT cells treated with 2DG when compared with B3. (C) To determine the effect of an inhibitor of IP3R1, 2APB, on formation of the IP3R1-GRP75-VDAC1 bridge, Grp75 labeling was attenuated in HBEC3-KT cells exposed to 2DG. Scale bar, 5 μm. (D) Effect of 2DG + 2APB and 2APB alone on cell killing in both HBEC3-KT and B3 cells. (E) Effect of the calcium mimetic, R568, on cell survival in the presence of 2DG. All data are plotted as mean ± SD. n = 3.

Figure 4

Mitochondrial function is defective in…

Figure 4

Mitochondrial function is defective in glucose-deprived ATM-deficient cells in response to nutrient stress…

Figure 4
Mitochondrial function is defective in glucose-deprived ATM-deficient cells in response to nutrient stress (A) Mitochondrial ROS was measured using MitoSox, a mitochondrial superoxide indicator. Basal levels of mitochondrial ROS were higher in B3 when compared with HBEC3-KT, and an increase was observed in both cell types exposed to 2DG. Increase in mitochondrial ROS was also observed following exposure to H2O2, which was used as a positive control. (B) Mitochondrial membrane potential was measured using JC-1. A significant increase in membrane potential was observed in B3 cells exposed to 2DG. Treatment with FCCP was used as a control to decrease membrane potential. (C) Mitochondrial mass as determined by the ratio of mtDNA to nDNA. (D) Analysis of mitophagy was performed using MtPhagy Dye (red) co-stained with MitoTracker (green). An increase in mitophagy was observed in HBECs exposed to 2DG but not in B3. Data are plotted as the mean ± SD. A minimum of 50 cells were analyzed. Scale bar, 5 μm. (E) BNIP expression in HBEC3-KT and B3 cells ± 2DG as a measure of mitophagy. (F) Immunoblotting for the detection of MFN2 and DRP1. α-Tubulin was used as a loading control. (G) Quantitation of Mfn2 band intensity. (H) Recruitment of p97 to mitochondria as determined by co-immunostaining with TOMM20. Scale bar, 5 μm. (I) Quantitation of perinuclear p97 rings in HBEC and B3 with and without 2DG treatment. (J) Immunoblotting of p97. VDAC1 was used as a loading control. (K and L) (K) Mitochondrial function analysis was performed using the Seahorse XF24 extracellular flux analyzer. Results showed a higher respiratory capacity in basal (upper) and 2DG-treated (lower) B3 cells when compared with HBEC cells in (L). All data are plotted as mean ± SD. n = 3, ∗p 
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References
    1. Abd Rahim M.S., Cherniavskyi Y.K., Tieleman D.P., Dames S.A. NMR- and MD simulation-based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated. J. Biol. Chem. 2019;294:7098–7112. - PMC - PubMed
    1. Ambrose M., Goldstine J.V., Gatti R.A. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum. Mol. Genet. 2007;16:2154–2164. - PubMed
    1. Bakkenist C.J., Kastan M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506. - PubMed
    1. Barzilai A., Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst) 2004;3:1109–1115. - PubMed
    1. Blignaut M., Loos B., Botchway S.W., Parker A.W., Huisamen B. Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation. Sci. Rep. 2019;9:4782. - PMC - PubMed
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Figure 2
Figure 2
Defect in ER-mitochondrial interaction in ATM-deficient cells (A) Electron microscopy of HBEC3-KT and B3 cells with and without exposure to 2DG. A distance of ≤25 nm between mitochondria and ER is considered as a contact site. Each contact site is highlighted in pink. An increase in the number of contact sites were observed in HBEC3-KT cells exposed to 2DG, whereas the opposite was observed for B3. (B) Quantitation of the number of contact sites between mitochondria and ER in HBEC3-KT and B3 cells in the presence or absence of 2DG performed in a blind fashion. (C and D) (C) Co-staining using an antibody against Grp75 (green) and MitoTracker (red) was performed on HBEC3-KT and B3 cells in the presence or absence of 2DG. An increase in the fluorescence intensity was observed in HBEC3-KT cells following exposure to 2DG but not in B3. These data are quantitated in (D). Scale bar, 5 μm. (E) Immunoblotting for Grp75, IPR1, and VDAC1 in cells following exposure to 2DG showed no differences in protein levels between HBEC3-KT and B3. This suggested a change in Grp75 localization in 2DG-treated HBEC3-KT cells and not an increase in protein levels. α-Tubulin was used as a loading control. (F and G) (F) Proximity ligation assay (PLA) using antibodies against IP3R1 (ER) and GRP75 (mitochondria) was performed as a means of showing increased interaction between GRP75 and IP3R1. An increase in the number of foci in HBEC3-KT cells following exposure to 2DG was observed. Quantitation of these data is shown in (G). Scale bar, 5 μm. Appropriate negative control with no primary antibody was performed. All data are plotted as a mean ± SD. n = 3, ∗p 

Figure 3

Defect in Ca 2+ transfer…

Figure 3

Defect in Ca 2+ transfer between ER and mitochondria in ATM-deficient cells in…

Figure 3
Defect in Ca2+ transfer between ER and mitochondria in ATM-deficient cells in response to glucose deprivation (A) Intracellular calcium was measured using FURA-2 as a calcium indicator. A significant increase in calcium was observed in HBEC3-KT cells treated with 2DG when compared with B3. (B) Mitochondrial calcium was measured using Rhodamine-2AM. Similar to results observed with FURA-2, a significant increase in calcium was seen in HBEC3-KT cells treated with 2DG when compared with B3. (C) To determine the effect of an inhibitor of IP3R1, 2APB, on formation of the IP3R1-GRP75-VDAC1 bridge, Grp75 labeling was attenuated in HBEC3-KT cells exposed to 2DG. Scale bar, 5 μm. (D) Effect of 2DG + 2APB and 2APB alone on cell killing in both HBEC3-KT and B3 cells. (E) Effect of the calcium mimetic, R568, on cell survival in the presence of 2DG. All data are plotted as mean ± SD. n = 3.

Figure 4

Mitochondrial function is defective in…

Figure 4

Mitochondrial function is defective in glucose-deprived ATM-deficient cells in response to nutrient stress…

Figure 4
Mitochondrial function is defective in glucose-deprived ATM-deficient cells in response to nutrient stress (A) Mitochondrial ROS was measured using MitoSox, a mitochondrial superoxide indicator. Basal levels of mitochondrial ROS were higher in B3 when compared with HBEC3-KT, and an increase was observed in both cell types exposed to 2DG. Increase in mitochondrial ROS was also observed following exposure to H2O2, which was used as a positive control. (B) Mitochondrial membrane potential was measured using JC-1. A significant increase in membrane potential was observed in B3 cells exposed to 2DG. Treatment with FCCP was used as a control to decrease membrane potential. (C) Mitochondrial mass as determined by the ratio of mtDNA to nDNA. (D) Analysis of mitophagy was performed using MtPhagy Dye (red) co-stained with MitoTracker (green). An increase in mitophagy was observed in HBECs exposed to 2DG but not in B3. Data are plotted as the mean ± SD. A minimum of 50 cells were analyzed. Scale bar, 5 μm. (E) BNIP expression in HBEC3-KT and B3 cells ± 2DG as a measure of mitophagy. (F) Immunoblotting for the detection of MFN2 and DRP1. α-Tubulin was used as a loading control. (G) Quantitation of Mfn2 band intensity. (H) Recruitment of p97 to mitochondria as determined by co-immunostaining with TOMM20. Scale bar, 5 μm. (I) Quantitation of perinuclear p97 rings in HBEC and B3 with and without 2DG treatment. (J) Immunoblotting of p97. VDAC1 was used as a loading control. (K and L) (K) Mitochondrial function analysis was performed using the Seahorse XF24 extracellular flux analyzer. Results showed a higher respiratory capacity in basal (upper) and 2DG-treated (lower) B3 cells when compared with HBEC cells in (L). All data are plotted as mean ± SD. n = 3, ∗p 
Similar articles
Cited by
References
    1. Abd Rahim M.S., Cherniavskyi Y.K., Tieleman D.P., Dames S.A. NMR- and MD simulation-based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated. J. Biol. Chem. 2019;294:7098–7112. - PMC - PubMed
    1. Ambrose M., Goldstine J.V., Gatti R.A. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum. Mol. Genet. 2007;16:2154–2164. - PubMed
    1. Bakkenist C.J., Kastan M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506. - PubMed
    1. Barzilai A., Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst) 2004;3:1109–1115. - PubMed
    1. Blignaut M., Loos B., Botchway S.W., Parker A.W., Huisamen B. Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation. Sci. Rep. 2019;9:4782. - PMC - PubMed
Show all 71 references
Related information
[x]
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Copy Download .nbib
Format: AMA APA MLA NLM
Figure 3
Figure 3
Defect in Ca2+ transfer between ER and mitochondria in ATM-deficient cells in response to glucose deprivation (A) Intracellular calcium was measured using FURA-2 as a calcium indicator. A significant increase in calcium was observed in HBEC3-KT cells treated with 2DG when compared with B3. (B) Mitochondrial calcium was measured using Rhodamine-2AM. Similar to results observed with FURA-2, a significant increase in calcium was seen in HBEC3-KT cells treated with 2DG when compared with B3. (C) To determine the effect of an inhibitor of IP3R1, 2APB, on formation of the IP3R1-GRP75-VDAC1 bridge, Grp75 labeling was attenuated in HBEC3-KT cells exposed to 2DG. Scale bar, 5 μm. (D) Effect of 2DG + 2APB and 2APB alone on cell killing in both HBEC3-KT and B3 cells. (E) Effect of the calcium mimetic, R568, on cell survival in the presence of 2DG. All data are plotted as mean ± SD. n = 3.
Figure 4
Figure 4
Mitochondrial function is defective in glucose-deprived ATM-deficient cells in response to nutrient stress (A) Mitochondrial ROS was measured using MitoSox, a mitochondrial superoxide indicator. Basal levels of mitochondrial ROS were higher in B3 when compared with HBEC3-KT, and an increase was observed in both cell types exposed to 2DG. Increase in mitochondrial ROS was also observed following exposure to H2O2, which was used as a positive control. (B) Mitochondrial membrane potential was measured using JC-1. A significant increase in membrane potential was observed in B3 cells exposed to 2DG. Treatment with FCCP was used as a control to decrease membrane potential. (C) Mitochondrial mass as determined by the ratio of mtDNA to nDNA. (D) Analysis of mitophagy was performed using MtPhagy Dye (red) co-stained with MitoTracker (green). An increase in mitophagy was observed in HBECs exposed to 2DG but not in B3. Data are plotted as the mean ± SD. A minimum of 50 cells were analyzed. Scale bar, 5 μm. (E) BNIP expression in HBEC3-KT and B3 cells ± 2DG as a measure of mitophagy. (F) Immunoblotting for the detection of MFN2 and DRP1. α-Tubulin was used as a loading control. (G) Quantitation of Mfn2 band intensity. (H) Recruitment of p97 to mitochondria as determined by co-immunostaining with TOMM20. Scale bar, 5 μm. (I) Quantitation of perinuclear p97 rings in HBEC and B3 with and without 2DG treatment. (J) Immunoblotting of p97. VDAC1 was used as a loading control. (K and L) (K) Mitochondrial function analysis was performed using the Seahorse XF24 extracellular flux analyzer. Results showed a higher respiratory capacity in basal (upper) and 2DG-treated (lower) B3 cells when compared with HBEC cells in (L). All data are plotted as mean ± SD. n = 3, ∗p 

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