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Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice

Nature Metabolism volume 5, pages 2220–2236 (2023)Cite this article

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Abstract

Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.

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Fig. 1: Chronic stress induces mitochondrial fission in the mPFC of mice.
Fig. 2: Chronic stress increases Drp1-dependent mitochondrial fission in the mPFC of mice.
Fig. 3: Mitochondrial Drp1 recruitment leads to the deficits of spine morphology and synaptic transmission in the mPFC of mice.
Fig. 4: Neuronal mitochondrial fission mediates depressive-like behavior.
Fig. 5: Drp1-dependent mitochondrial fission weakens synaptic transmission by disturbing the coupling of mitochondrial respiratory chain.
Fig. 6: Pharmacological inhibition of mitochondrial fission alleviates the impairment of synaptic transmission and depressive-like behavior.
Fig. 7: Mitochondrial fission regulates synaptic energy adaptation.

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The data that support the finding of this study are provided within this paper and its supplementary information. Source data are provided with this paper.

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Acknowledgements

This work was supported by the Foundation for National Key R&D Program of China (STI2030-Major Projects, grant no. 2021ZD0202900 to J.-G.C.), National Natural Science Foundation of China (grant no. 82130110 to J.-G.C. and grant no. U21A20363 to F.W.), National Natural Science Foundation of China (no. 81872849 to L.-H.L., no. 81971279 to F.W. and no. 81973310 to J.-G.C.) and the Innovative Research Groups of National Natural Science Foundation of China (grant no. 81721005 to J.-G.C. and F.W.). The authors are grateful to W.-K. Ji for the plasmid mCherry-mito-7.

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Author notes

  1. These authors contributed equally: Wan-Ting Dong, Li-Hong Long.

Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang & Jian-Guo Chen

  2. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China

    Li-Hong Long, Fang Wang & Jian-Guo Chen

  3. The Research Center for Depression, Tongji Medical College, Huazhong University of Science, Wuhan, China

    Li-Hong Long, Fang Wang & Jian-Guo Chen

  4. The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China

    Li-Hong Long, Fang Wang & Jian-Guo Chen

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  1. Wan-Ting Dong
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Contributions

J.-G.C., F.W. and L.-H.L. designed the experiment and directed the study. W.-T.D. performed the experiments. W.-T.D., L.-H.L. and Q.D. analyzed data and W.-T.D. and L.-H.L. wrote the manuscript. D.L. and J.-L.W. made CSDS models and performed the behavioral tests.

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Correspondence to Fang Wang or Jian-Guo Chen.

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Extended data

Extended Data Fig. 1 Chronic stress has no significant effect on mitochondrial function of resilient mice.

a-c, Typical heat plot of social interaction test (a), social interaction ratio (b), time in interaction zone (c), time in corner zone (d) and sucrose preference (e). N = 10 mice for control and N = 12 mice for resilient. f, Pie chart showing the percentage of eligible and ineligible control mice. N = 519 mice for control and N = 893 mice for CSDS. g, h, Spontaneous activity of mice in open-field test (OFT). N = 54 mice for control and N = 73 mice for CSDS. i, j, Pie chart showing the percentage of mice with immobility time more than 90 s in the forced swim test (FST). N = 54 mice for control and N = 73 mice for CSDS. k, l, Pie chart showing the percentage of mice with immobility time more than 90 s in the tail suspension test (TST). N = 54 mice for control and N = 73 mice for CSDS. m, Timelines of experimental procedure, selection of resilient mice after exposure to CSDS, extraction of mitochondria to detect the mitochondrial membrane potential and ATP. n, JC-1 detection of mitochondrial membrane potential in control and resilient mice. N = 6 mice for each group. o, Bioluminescence kit to observe mitochondrial ATP level. N = 5 mice for control and N = 7 mice for resilient. p, Representative electron microscope graphs indicating the mitochondrial morphology and quantitative analysis of the relative length from fission site to the tip of a mitochondrion. N = 6 mice for each group, white line depicts the mitochondrial edges and white arrows represent fission site. Scale bar represents 100 nm. q, Representative electron microscope graphs and quantitative analysis of tiny mitochondria. N = 6 mice for control and N = 6 mice for resilient, white line depicts the mitochondrial edges and white arrows represent tiny mitochondria. Scale bar represents 500 nm. Data are represented as means ± s.e.m. Two-tailed Student’s t-tests for b, e, h, j, l and n-q. Two-way ANOVA followed by Bonferroni’s post hoc tests for c and d.

Source data

Extended Data Fig. 2 Chronic stress increases the level of phosphorylated Drp1 (p-Drp1) in the mPFC.

a, Double immunostaining for Tomm20 (Green) with AAV-mito-7-mCherry (AAV-mito, Red) (from 3 independent experiments). Scale bar represents 5 µm. b, Representative micrographs showing the mitochondrial morphology (from 3 independent experiments). Scale bar represents 5 µm (left) and 2 µm (top right). c, d, Double immunostaining (c) and quantitative analysis (d) for the NeuN (Red), Iba1 (Red) and GFAP (Red) with Drp1 (Green) in the mPFC. N = 7 brain slices from 4 mice. Scale bar represents 20 µm. e-g, The representative protein bands (e) and quantitative analysis of p-Drp1 (f) and Drp1 (g) in the mPFC. N = 23 mice for control, N = 24 mice for SUS and N = 11 mice for resilient. h,i, Mitochondrial membrane potential (h) and ATP level (i) in the nucleus accumbens (NAc). N = 6 mice for each group. j-l, The representative protein bands (j) and quantitative analysis of p-Drp1 (k) and Drp1 (l) in the NAc. N = 7 mice for control, N = 6 mice for SUS and resilient. m,n, Mitochondrial membrane potential (m) and ATP level (n) in the hippocampus. N = 6 mice for each group. o-q, The representative protein bands (o) and quantitative analysis of p-Drp1 (p) and Drp1 (q) in the Hippocampus. N = 7 mice for control, N = 6 mice for SUS and resilient. r,s, Mitochondrial membrane potential (r) and ATP level (s) in the lateral habenula (LHb). N = 6 mice for each group. t-v, The representative protein bands (t) and quantitative analysis of p-Drp1 (u) and Drp1 (v) in LHb. N = 7 mice for control, N = 6 mice for SUS and resilient. w, The glutamate concentration in the mPFC. N = 5 mice for each group. x, y, The representative protein bands (x) and quantitative analysis (y) of mitofusin 2 (Mfn2) in the mPFC. N = 6 mice for control, N = 7 mice for SUS. Data are represented as means ± s.e.m. Two-tailed Student’s t-tests for h, i, m, n, r, s, w and y. One-way ANOVA followed by Bonferroni’s post hoc tests for f, g, k, l, p, q, u and v.

Source data

Extended Data Fig. 3 Binding of Drp1 to Fis1 promotes stress susceptibility.

a, b, mRNA expression of mitochondrial fission protein 1 (Fis1) (a) and mitochondrial fission factor (Mff) (b). N = 8 mice for each group. c, Experimental timelines for P110 administration. d, The representative protein bands and quantitative analysis of mitochondrial Drp1 in the mPFC. N = 6 mice for TAT and N = 7 mice for P110. e,f, Mitochondrial membrane potential (e) and mitochondrial ATP level (f). N = 9 mice for each group. g, Experimental timelines for P110 administration, behavioral study and Co-immunoprecipitation (Co-IP) analysis. h,i, Co-IP analysis showing the interaction between Drp1 and Fis1 in the mPFC. N = 4 mixed samples from 12 mice for each group. j, Spontaneous activity of mice. N = 12 mice for each group. k-m, Typical heat plot (k) of social interaction test, social interaction ratio, time spent in interaction zone and corner zone (l), and sucrose preference (m). N = 12 mice for each group. n, Experiment timeline for P110 pre-administration and behavioral study. o, Spontaneous activity of mice. N = 8 mice for control + TAT and control + P110, N = 9 mice for CSDS + TAT and CSDS + P110. p, q, Typical heat plot (p) of social interaction test, social interaction ratio, time spent in interaction zone and time spent in corner zone (q). N = 8 mice for control + TAT and control + P110, N = 9 mice for CSDS + TAT and CSDS + P110. r, The proportion of social interaction deficient mice. s, Sucrose preference test. N = 8 mice for control + TAT and control + P110, N = 9 mice for CSDS + TAT and CSDS + P110. t, Experiment timeline for behavioral test. u, Spontaneous activity of mice. N = 10 mice for each group. v-x, The depressive-like behavior was evaluated by social interaction test (v, w), and sucrose preference test (x). N = 10 mice for each group. Data are represented as means ± s.e.m. Two-tailed Student’s t-tests for a, b and d-f. Two-way ANOVA followed by Bonferroni’s post hoc tests for j, l, m, o, q, s, u, w, x and Tukey’s post hoc tests for i.

Source data

Extended Data Fig. 4 Drp1 knockdown rescues the inhibition of excitatory synaptic transmission.

a, b, The depressive-like behavior was evaluated by social interaction test (a) and sucrose preference test (b) after LV-Dnm1l-RNAi [LV-Dnm1l (Ri)] infusion. N = 33 mice for control + LV-GFP (GFP), N = 35 mice for susceptible (SUS) + GFP, N = 31 mice for control + Dnm1l (Ri) and N = 33 mice for SUS + Dnm1l (Ri). c-e, Representative traces of AMPAR-mediated miniature excitatory postsynaptic currents (mEPSCs) recordings after Dnm1l (Ri) injection (c). The mEPSCs amplitude scatter diagram (upper panel) and cumulative plots (bottom panel, d), and mEPSCs frequency scatter diagram (upper panel) and cumulative plots (bottom panel, e) for representative cells. N = 9 cells from 5 mice for control + GFP, N = 11 cells from 5 mice for SUS + GFP, N = 9 cells from 5 mice for control + Dnm1l (Ri) and N = 14 cells from 6 mice for SUS + Dnm1l (Ri). f-h, Representative traces of miniature inhibitory postsynaptic currents (mIPSCs) recordings after Dnm1l (Ri) injection (f). The mIPSCs amplitude scatter diagram (upper panel) and cumulative plots (bottom panel, g), and mIPSCs frequency scatter diagram (upper panel) and cumulative plots (bottom panel, h) for representative cells. N = 7 cells from 4 mice for control + GFP, N = 6 cells from 3 mice for SUS + GFP, N = 6 cells from 3 mice for control + Dnm1l (Ri) and N = 11 cells from 5 mice for SUS + Dnm1l (Ri). Data are represented as means ± s.e.m. Two-way ANOVA followed by Bonferroni’s post hoc tests for a, b, d, e, g and h.

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Extended Data Fig. 5 Drp1 knockdown reverses the mRNA expression of OMA1/DELE1/HRI in susceptible mice.

a, b, The depressive-like behavior was evaluated by social interaction test (a) and sucrose preference test (b) after LV-Dnm1l-RNAi [LV-Dnm1l (Ri)] infusion. N = 18 mice for control + LV-GFP (GFP), N = 19 mice for susceptible (SUS) + GFP, N = 21 mice for control + Dnm1l (Ri) and N = 22 mice for SUS + Dnm1l (Ri). c-e, The mRNA level of mitochondrial protease OMA1 (c), DAP3 binding cell death enhancer 1 (DELE1) (d) and eukaryotic translation initiation factor 2α kinase (HRI) (e) after Dnm1l (Ri) injection. N = 6 mice for control + GFP, N = 6 mice for SUS + GFP, N = 7 mice for control + Dnm1l (Ri) and N = 7 mice for SUS + Dnm1l (Ri). f, g, The time in the interaction zone (f) and corner zone (g) during the no target phase of social interaction test of mice. N = 8 mice for control + GFP, N = 10 mice for SUS + GFP, N = 7 mice for control + Dnm1l (Ri) and N = 10 mice for SUS + Dnm1l (Ri). Data are represented as means ± s.e.m. Two-way ANOVA followed by Bonferroni’s post hoc tests for a-g.

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Extended Data Fig. 6 Norepinephrine and oligomycin A differentially decreases mitochondrial ATP.

a, Norepinephrine moderately dissipates mitochondrial ATP in N2A cell. N = 6 well for each group. b, c, the time in interaction zone (b) and corner zone of mice (c) during the no target phase of social interaction test. N = 12 mice for each group. d, Oligomycin A continuously inhibits mitochondrial ATP in N2A cell. N = 6 well for each group. e-g, The time in interaction zone during the target phase of social interaction test (e), and time in interaction zone (f) and corner zone (g) during the no target phase of social interaction test of mice. N = 14 mice for control + LV-GFP (GFP), N = 12 mice for susceptible (SUS) + GFP, N = 13 mice for control + LV-Dnm1l-RNAi [Dnm1l (Ri)] and N = 12 mice for SUS + Dnm1l (Ri). Data are represented as means ± s.e.m. One-way ANOVA followed by Bonferroni’s post hoc tests for a and d. Two-way ANOVA followed by Bonferroni’s post hoc tests for b, c and e-g.

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Extended Data Fig. 7 Mdivi1 reduces ROS release and rescues Drp1 recruitment to mitochondria in susceptible mice.

a, Experimental timelines for glucose administration and behavioral study, susceptible (SUS) mice were selected for implanting cannula into the mPFC, and behavioral test was performed after glucose administration. b-d, Schematic and typical heat plot of mice in social interaction test (b), social interaction ratio, time in interaction zone, time in corner zone (c) and sucrose preference test (d). N = 7 mice for control + vehicle, N = 6 mice for SUS + vehicle, N = 7 mice for control + glucose and N = 6 mice for SUS + glucose. e, Spontaneous activity of mice in open-field test (OFT). N = 7 mice for control + vehicle, N = 6 mice for SUS + vehicle, N = 7 mice for control + glucose and N = 6 mice for SUS + glucose. f, Representative micrographs showing immunostaining for dihydropyridine (DHE) (Red, representing mitochondrial ROS), NeuN (Green) and DAPI (Blue), and the quantification of mitochondrial ROS in control and SUS mice. N = 3 mice each group. Scale bar represents 20 µm. g, Representative micrographs showing the recruitment of Drp1 to mitochondria in the mPFC of SUS + vehicle and SUS + Mdivi1 mice (from 3 independent experiments). Scale bar represents 5 µm. h-j, mRNA expression of mitochondrial protease OMA1 (h), DAP3 binding cell death enhancer 1 (DELE1) (i) and eukaryotic translation initiation factor 2α kinase (HRI) (j). N = 10 mice for each group. Data are represented as means ± s.e.m. Two-tailed Student’s t-tests for f. Two-way ANOVA followed by Bonferroni’s post hoc tests for c-e and h-j.

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Supplementary Tables 1–5 and uncropped scans of all blots.

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Dong, WT., Long, LH., Deng, Q. et al. Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice. Nat Metab 5, 2220–2236 (2023). https://doi.org/10.1038/s42255-023-00924-6

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