Molecular Neurobiology

, Volume 56, Issue 8, pp 5586–5607 | Cite as

Neuroprotective Mitochondrial Remodeling by AKAP121/PKA Protects HT22 Cell from Glutamate-Induced Oxidative Stress

  • Jingdian Zhang
  • Jiachun Feng
  • Di Ma
  • Feng Wang
  • Yumeng Wang
  • Chunxiao Li
  • Xu Wang
  • Xiang Yin
  • Ming Zhang
  • Ruben K. Dagda
  • Ying ZhangEmail author


Protein kinase A (PKA) is a ser/thr kinase that is critical for maintaining essential neuronal functions including mitochondrial homeostasis, bioenergetics, neuronal development, and neurotransmission. The endogenous pool of PKA is targeted to the mitochondrion by forming a complex with the mitochondrial scaffold A-kinase anchoring protein 121 (AKAP121). Enhanced PKA signaling via AKAP121 leads to PKA-mediated phosphorylation of the fission modulator Drp1, leading to enhanced mitochondrial networks and thereby blocking apoptosis against different toxic insults. In this study, we show for the first time that AKAP121/PKA confers neuroprotection in an in vitro model of oxidative stress induced by exposure to excess glutamate. Unexpectedly, treating mouse hippocampal progenitor neuronal HT22 cells with an acute dose or chronic exposure of glutamate robustly elevates PKA signaling, a beneficial compensatory response that is phenocopied in HT22 cells conditioned to thrive in the presence of excess glutamate but not in parental HT22 cells. Secondly, redirecting the endogenous pool of PKA by transiently transfecting AKAP121 or transfecting a constitutively active mutant of PKA targeted to the mitochondrion (OMM-PKA) or of an isoform of AKAP121 that lacks the KH and Tudor domains (S-AKAP84) are sufficient to significantly block cell death induced by glutamate toxicity but not in an oxygen deprivation/reperfusion model. Conversely, transient transfection of HT22 neuronal cells with a PKA-binding-deficient mutant of AKAP121 is unable to protect against oxidative stress induced by glutamate toxicity suggesting that the catalytic activity of PKA is required for AKAP121’s protective effects. Mechanistically, AKAP121 promotes neuroprotection by enhancing PKA-mediated phosphorylation of Drp1 to increase mitochondrial fusion, elevates ATP levels, and elicits an increase in the levels of antioxidants GSH and superoxide dismutase 2 leading to a reduction in the level of mitochondrial superoxide. Overall, our data supports AKAP121/PKA as a new molecular target that confers neuroprotection against glutamate toxicity by phosphorylating Drp1, to stabilize mitochondrial networks and mitochondrial function and to elicit antioxidant responses.


Protein kinase A A-kinase anchoring protein 121 Dynamin-related protein 1 (Drp1) Oxidative stress HT22 Mitochondrion 



Superoxide dismutase 2


Total glutathione


A-kinase anchor protein 121


Cyclic adenosine monophosphate


cAMP response element-binding protein


Dynamin-related protein 1


Dual specificity A-kinase anchoring protein 1



We thank Dr. Antonio Feliciello (Department of Molecular Medicine & Medical Biotechnology, University of Naples, Naples, Italy), Xingshun Xu (Institute of Neuroscience, Soochow University, China), Steven Green (Biology Department, University of Iowa, IA, USA), and Stefan Strack (Department of Pharmacology, University of Iowa Carver College of Medicine, IA, USA) for providing vectors and the HT22 cell line. We apologize to all colleagues whose important contributions to this field could not be cited due to space limitations.

Availability of Data and Materials

The raw data files used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ Contributions

Conceptualization and design of the study: Jingdian Zhang, Ming Zhang, Dagda RK, and Ying Zhang; methodology and investigation: Jingdian Zhang, Dagda RK, Feng Wang, Yumeng Wang, Xu Wang, Di Ma, Xiang Yin, Chunxiao Li; providing important research resources, materials, and scientific input: Jiachun Feng, Dagda RK, Ming Zhang, and Ying Zhang; writing the original manuscript draft: Jingdian Zhang and Dagda RK; review and editing: all authors; supervision: Ming Zhang, Dagda RK, Jiachun Feng, and Ying Zhang. All authors read and approved the final manuscript.


This work was supported by the Natural Science Foundation of Jilin Province Science and Technology Development Plan (No. 20180101154JC) (to Ying Zhang), by NIH grants 1R01NS105783-01 and GM103554 (to Ruben K. Dagda), National Natural Science Foundation of China (No. 81771257) (to Jiachun Feng), and National Natural Science Foundation for Young Scientists of China (No. 81701158) (to Di Ma).

Compliance with Ethical Standards

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2018_1464_Fig8_ESM.png (1.9 mb)
Supplementary figure S1

Transfection with the indicated vectors had no effects on basal cell viability and H89 treatment can block S-AKAP84’s promotion on mitochondrial interconnectivity and content. (A) Effects of vector transfection on HT22 cell viability under baseline situation. Cell transfection procedures see in Material and methods. Transfected cells were seeded in 96 well culture plates at 5000 cells/well, and 24 h later, cell viability was determined using the cck-8 assay. Vectors used in this experiment had no effects on cell viability in normal situation. (B) H89 can block the protection of AKAP121 on HT22 in oxidative insults while it had no effects on HT22 cell viability under baseline conditions. (C) HT22 cells transiently transfected OMM-GFP, S-AKAP84 and S-AKAP84 with 1umH89 for 4 hr were stained with 30 nm MitoTracker Red and 2 μg/ml Hoechst 33342 for 15 min at 37 °C to visualize mitochondria and nuclei. Incubation with 1μm H89 for 4 hours had blocked the mitochondrial pro-fusion effects of S-AKAP84. Scale bar = 10 μm. (D) Quantification of mitochondrial interconnectivity and content of three groups in which HT22 cells transiently transfected OMM-GFP, S-AKAP84 and S-AKAP84 with 1μmH89 for 4 hours. (*:p < 0.05, **:p < 0.01, ***:p < 0.001 One-Way ANOVA, Tukey’s test). (E) Cells lysates derived from HT22-sensitive and-resistance cell clones (HT22-R) and HT22-R incubated in 1 μM or 10 μM H89 for 24 h were immunoblotted for endogenous AKAP121, p-CREB and CREB to analyze the extent to which exposure of cells to chronic and high concentrations of glutamate elicits PKA signaling and whether H89 can block this signaling. The bar graphs on the right show imaged based quantifications of the mean intensity of the immunoreactive bands for AKAP121 (left bar graph) or of p-CREB/T-CREB ratio. (For both graphs (*:p < 0.05, **:p < 0.01, ***:p < 0.001 One-Way ANOVA, Tukey’s test). All the data were pooled from experiments that were repeated at least three times which yielded similar results (a representative data set is shown). (PNG 1897 kb)

12035_2018_1464_MOESM1_ESM.tif (42.3 mb)
High resolution image (TIF 43327 kb)
12035_2018_1464_Fig9_ESM.png (1.6 mb)
Supplementary figure S2

AKAP121/PKA signaling is crucial for HT22-R cells to maintain mitochondrial interconnectivity and content. (A) HT22-R cells transfected with rat AKAP121-WT and rat AKAP121-△PKA were stained with 30 nm MitoTracker Red and 2 μg/ml Hoechst 33342 for 15 min at 37 °C to visualize mitochondria and nuclei respectively. The data show that the ability of AKAP121 to bind PKA is essential for its mitochondrial pro-fusion activity in HT22-R cell clones. Scale bar = 10 μm. (B-C) Quantification of mitochondrial interconnectivity and content of the two groups in which HT22-R cells transiently transfected rat AKAP121-WT and AKAP121-△PKA plasmids. For both panels (***:p < 0.001, vs. HT22-R-AKAP121-WT, Student t-test). (D-E) Cell viability assay of HT22-R and HT22-S cells that overexpressed OMM-GFP, rat AKAP121-WT and rat AKAP121-ΔPKA plasmids. HT22-R cell line was maintained in 10 mM glutamate while parental HT22 cells were challenged with 4 mM glutamate for 24 h. The data shows that the ability of AKAP121 to bind PKA is essential for its neuroprotection against oxidative stress. (**:p < 0.01, ***:p < 0.001 vs. con One-Way ANOVA, Tukey’s test). (F) Transfected HT22 cells were exposed to 4 mM glutamate for the indicated time points and stained with 5 μM MitoSOX Red, then subjected to immunofluorescence microscopy analyses. All the data were pooled from experiments that were repeated at least three times which yielded similar results (a representative data set is shown). (PNG 1615 kb)

12035_2018_1464_MOESM2_ESM.tif (34.4 mb)
High resolution image (TIF 35179 kb)
12035_2018_1464_Fig10_ESM.png (3.1 mb)
Supplementary figure S3

HT22 cells with enhanced AKAP121/PKA signaling can maintain a high mitochondrial interconnectivity and content in 2 h glutamate insult.A. HT22 cells were transfected with OMM-GFP control or with AKAP121-WT, AKAP121-ΔPKA, and Drp1-S656D for 24 h. and subjected to 4 mM glutamate insults for 2 hours. Cells were stained with 30 nM MitoTracker Red and 2 μg/ml Hoechst 33342 for 15 min at 37 °C to visualize mitochondria and nuclei respectively under baseline conditions. Fluorescent images were captured through the midplane of the soma by employing a DeltaVision Elite Live cell Imaging System (a.e.i.m.q. MitoTracker Red; b.f.j.n.r. EGFP; c.g.k.o.s. Merged image of three colors; d.h.i.p.t. Hoechst33342 with bright-field reference) Scale bar = 10 μm. B. Quantification of mitochondrial interconnectivity (area/perimeter ratio per cell) in HT22 cells transiently expressing AKAP121-WT,AKAP121-△PKA,Drp1-S656D and OMM-GFP and incubated with 4 mM glutamate for 2 h.(**:p < 0.01, ***:p < 0.001 One-Way ANOVA, Tukey’s test). C. Quantification of mitochondrial content (% of cytosol occupied by mitochondria) in HT22 cells transiently expressing AKAP121-WT, AKAP121-△PKA, Drp1-S656D and OMM-GFP and incubated for with 4 mM glutamate for 2 h. (*:p < 0.05, **:p < 0.01, One-Way ANOVA, Tukey’s test). D. Quantification of mitochondrial interconnectivity (area/perimeter ratio per cell) in HT22 cells incubated with 4 mM glutamate for 0, 2, or 4 hours. (**:p < 0.01,***:p < 0.001 One-Way ANOVA, Tukey’s test). E. Quantification of mitochondrial content (% of cytosol occupied by mitochondria) in HT22 cells incubated with 4 mM glutamate for 0, 2, or 4 hours. (***:p < 0.001, One-Way ANOVA, Tukey’s test). (PNG 3224 kb)

12035_2018_1464_MOESM3_ESM.tif (15.4 mb)
High resolution image (TIF 15782 kb)
12035_2018_1464_Fig11_ESM.png (180 kb)
Supplementary figure S4

AKAP121/PKA signaling is crucial for mitochondrial membrane potential and ATP generation. (A-C) HT22 cells from three groups, transfected with pcDNA3.1, AKAP121 and AKAP121 with 1 μM H89 for 4 h, stained with Rhodamine-123 (5 μM, 37 °C for 30 min), then subjected to flow cytometry to analyze for mitochondrial membrane potential. (D) The bar graphs show the level of mitochondrial membrane potential between control group and cells transfected with AKAP121. (E) Quantification of mitochondrial membrane potential in cells transfected with pcDNA3.1, AKAP121 and AKAP121 with 1 μM H89 for 4 h. H89 partly blocked MMP elevation induced by AKAP121 overexpression. (**:p < 0.01,***:p < 0.001 One-Way ANOVA, Tukey’s test). (F) We used FCCP to determine the level of mitochondrial ATP generated in HT22 cells, right panel: AKAP121-WT overexpression group had a higher mitochondrial-ATP content. (*:p < 0.05,**:p < 0.01,vs. OMM-GFP, Student t-test). Meanwhile, H89 treatment can also decrease total ATP content in AKAP121 overexpression group.(**:p < 0.01, vs. AKAP121-WT, Student t-test) All the data were pooled from experiments that were repeated at least three times which yielded similar results (a representative data set is shown). (PNG 180 kb)

12035_2018_1464_MOESM4_ESM.tif (16 mb)
High resolution image (TIF 16362 kb)
12035_2018_1464_MOESM5_ESM.avi (6.3 mb)
video S1 Easy 3D reconstruction videos of parental HT22 cells transfected with OMM-GFP, generated by biplane .imaris.v7.4.2. (AVI 6406 kb)
12035_2018_1464_MOESM6_ESM.avi (6.8 mb)
video S2 Easy 3D reconstruction videos of parental HT22 cells transfected with S-AKAP84, generated by biplane .imaris.v7.4.2. (AVI 6946 kb)
12035_2018_1464_MOESM7_ESM.avi (4.7 mb)
video S3 Easy 3D reconstruction videos of parental HT22 cells transfected with OMM-PKA, generated by biplane .imaris.v7.4.2. (AVI 4810 kb)
12035_2018_1464_MOESM8_ESM.avi (9.9 mb)
video S4 Easy 3D reconstruction videos of parental HT22 cells transfected with Drp1-S656D, generated by biplane .imaris.v7.4.2. (AVI 10116 kb)
12035_2018_1464_MOESM9_ESM.avi (9 mb)
video S5 Easy 3D reconstruction videos of parental HT22 cells transfected with AKAP121-WT, generated by biplane .imaris.v7.4.2. (AVI 9165 kb)
12035_2018_1464_MOESM10_ESM.avi (7 mb)
video S6 Easy 3D reconstruction videos of parental HT22 cells transfected with AKAP121-△PKA, generated by biplane .imaris.v7.4.2. (AVI 7140 kb)
12035_2018_1464_MOESM11_ESM.avi (6.6 mb)
video S7 Easy 3D reconstruction videos of HT22-resistant cells transfected with AKAP121-WT, generated by biplane .imaris.v7.4.2. (AVI 6757 kb)
12035_2018_1464_MOESM12_ESM.avi (9.8 mb)
video S8 Easy 3D reconstruction videos of HT22-resistant cells transfected with AKAP121-△PKA, generated by biplane .imaris.v7.4.2. (AVI 10031 kb)


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Copyright information

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Authors and Affiliations

  1. 1.Department of Neurology and Neuroscience CenterFirst Hospital of Jilin UniversityChangchunChina
  2. 2.National-Local Joint Engineering Laboratory of Animal Models for Human DiseasesChangchunChina
  3. 3.Department of Physiology, College of Basic Medical Sciences, Norman Bethune Health Science CenterJilin UniversityChangchunChina
  4. 4.Department of Pharmacology, College of Basic Medical SciencesJilin UniversityChangchunChina
  5. 5.Department of Pharmacology, Reno School of MedicineUniversity of NevadaRenoUSA

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