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Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Nature Metabolism volume 6, pages 1492–1504 (2024)Cite this article

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Abstract

Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer’s disease and the response to demyelinating injury1,2,3,4,5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7,8,9,10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

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Fig. 1: Mitochondrial RC is not necessary for microglia proliferation.
Fig. 2: Microglial RC loss and ageing have distinct RNA signatures.
Fig. 3: Mitochondrial complex III function is required for remyelination following cuprizone treatment.
Fig. 4: Microglial mitochondrial complex III function is not required for control of Aβ plaque deposition or progression of memory deficits in AD.

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Data availability

Raw data for RNA-seq and metabolomics have been deposited in public databases. RNA-seq raw data can be accessed in the Gene Expression Omnibus under accession code GSE269239. The metabolomics raw data can be accessed at the Metabolomics Workbench under study ID ST003249. Source data are provided with this paper.

Code availability

High-level analysis was performed using custom scripts available in the NUPulmonary/utils GitHub repository.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) grants 2P01AG049665-06 to (N.S.C.), 2T32AI083216-11 to (J.S.S.) and 5T32HL076139-18 to (T.A.P.). Imaging work was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Flow cytometric analysis was supported by the Northwestern University Flow Cytometry Core Facility supported by NCI CCSG P30 CA060553. Flow cytometry cell sorting was performed on a BD FACSAria SORP and the MACSQuant Tyto systems, purchased through the support of NIH grant 1S10OD011996-01. Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. MRI imaging was performed at the CTI Small Animal Imaging Core. The Morris water maize was performed at the Behavioural Phenotyping Core, while the rotarod, grip strength, open-field and Barnes maze tests were performed in the tissue and neurobehaviour phenotyping core as part of the NHLBI programme under grant no. 2P01AG049665-06. We thank H. Abdala-Valencia and the Pulmonary NextGen Sequencing Core for RNA sequencing.

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Authors and Affiliations

  1. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Joshua S. Stoolman, Rogan A. Grant, Taylor A. Poor, Samuel E. Weinberg, Karis B. D’Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E. Zerrer, Walter A. Wood, Madeline C. Harding, Sahil Soni, Karen M. Ridge, Paul T. Schumacker, G. R. Scott Budinger & Navdeep S. Chandel

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Contributions

Conceptualization was the responsibility of J.S.S. and N.S.C. Funding acquisition was the responsibility of N.S.C., K.M.R. and G.S.B. Investigation was carried out by J.S.S., R.A.G., T.A.P., S.E.W., K.B.D., J.T., M.C.H., S.S., J.Y.H., M.E.Z. and W.A.W. Visualization was the responsibility of J.S.S. and R.A.G. Writing of the original draft was the responsibility of J.S.S. Review and editing of the manuscript was the responsibility of J.S.S., R.A.G., P.T.S., G.S.B. and N.S.C.

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Correspondence to Joshua S. Stoolman or Navdeep S. Chandel.

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Extended data

Extended Data Fig. 1 Tamoxifen treatment generates stable, RC-deficient microglia population.

(a) Schematic of generation of microglia-specific RISP-cKO mice using tamoxifen chow. (b) Flow plots from FACS-purified microglia and PCR results of DNA isolated from purified microglia examining RISP gene genotype. (c) Microglia directly ex vivo seahorse oxygen consumption readings at baseline RISP-cWT (n = 4), -cHET (n = 4) and -cKO (n = 4), coupled respiration after oligomycin (2 µM) injection (n = 3 for all groups as oligomycin injection failed in one run), uncoupled respiration after Bam15 (2 µm) injection and non-mitochondrial oxygen consumption after antimycin (1 µM) and piercidin (1 µM) injections. (d) Quantification of coupled respiration from seahorse data (n = 3 per group). For c and d data represent mean ± s.e.m. For d a Brown-Forsythe and Welch one-way ANOVA was performed with Dunnett’s T3 multiple comparisons test, with individual variances computed for each comparison.

Source data

Extended Data Fig. 2 Aged and RISP-cKO microglia have distinct transcriptional profiles.

Survival curves for (a) Males RISP-cHET (n = 5), RISP-cKO (n = 14) and (b) Females RISP-cHET (n = 11) and RISP-cKO (n = 22). (c) Normalized enrichment score from GSEA analysis of DAM, ISR, Hallmark Interferon Alpha Response and Hallmark TNF-α signialing via NF-κB comparing RISP-cKO n = 10 (M = 7, F = 3) and RISP-cHET 2-year-old n = 3 (M = 1, F = 2) to 1yr RISP-cHET n = 9 (M = 7, F = 2). (d) Venn Diagram comparing upregulated genes in RISP-cKO 1yr and RISP-cHET 2yr microglia from the DAM gene expression module. Enrichment score vs gene rank histograms of DAM modules in (e) RISP-cKO 1yr vs RISP-cHET 1yr and (f) RISP-cHET 2yr vs RISP-cHET 1yr. (g) Venn Diagram comparing upregulated genes in RISP-cKO 1yr and RISP-cHET 2yr microglia from the ISR gene expression module. Enrichment score vs gene rank histograms of ISR modules in (h) RISP-cKO 1yr vs RISP-cHET 1yr and (i) RISP-cHET 2yr vs RISP-cHET 1yr. Enrichment score vs gene rank histograms of Hallmark Interferon-α Response (MM3877) module in (j) RISP-cKO 1yr vs RISP-cHET 1yr and (k) RISP-cHET 2yr vs RISP-cHET 1yr. Enrichment score vs gene rank histograms of Hallmark Interferon-α Response (MM3877) module in (l) RISP-cKO 1yr vs RISP-cHET 1yr and (m) RISP-cHET 2yr vs RISP-cHET 1yr. (n) Percent of total time in center of open-field test conducted on 1-year-old RISP-cHET (n = 6) RISP-cKO (n = 11) and 2-year-old RISP-cHET (n = 6) mice. (o) Rotarod test of 1-year-old Het (n = 7), 1-year-old RISP-cKO (n = 16) and 2-year-old RISP-cHET (n = 10) mice. In a and b we used Kaplan-Meier tests with Manetl-Cox logrank and Gehan-Breslow-Wilcoxon test adding extra weight for early time points. In c-m enrichment analysis was then performed for all gene sets simultaneously using the ‘fgseaMultilevel’ method using gene-level Wald statistics as rankings and default parameters. For n and o we performed a one-way ANOVA with a Dunnett’s multiple comparisons test with a single pooled variance.

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Extended Data Fig. 3 Remyelination following cuprizone treatment requires mitochondrial complex III function in microglia.

(a) Representative MTR map of MRI images from RISP-cHET and RISP-cKO mice. White arrow in top right segment identifies the corpus callosum. (b) Axial section of MTR map with corpus callosum (green) and ventricle (red). (c) 3D rendering of corpus callosum and ventricle drawings used to quantify voxel intensity. (d) Odc-1 normalized mRNA counts from RISP-cHET and RISP-cKO microglia isolated from mice from two separate groups: from RISP-cHET and RISP-cKO microglia isolated from mice from two separate groups: 2 weeks into remyelination phase following cuprizone treatment RISP-cHET n = 4 (M = 2, F = 2), RISP-cKO n = 6 (M = 4, F = 2), aged 1-year RISP-cHET n = 9 (M = 7, F = 2) and RISP-cKO n = 10 (M = 7, F = 3), 1-year-old microglia data in this Fig is the same as Fig. 2. (e) Individual overlayed and individual fluorescent fields from Fig. 3b. In d a one-way ANOVA (followed by Tukey’s honest significant difference post-hoc test for multiple comparisons) was performed.

Source data

Extended Data Fig. 4 Microglial mitochondrial complex III function is not required for control of Aβ plaque deposition or progression of memory deficits in AD.

Average speed of mice in Morris water maze in (a) 4 month, (b) 9 month, and (c) 1 year hidden trials. 4 month Morris water maze (d) 4 months: RISP-cHET CTRL n = 6 (M = 3, F = 3), RISP-cKO CTRL n = 6 (M = 4, F = 2), RISP-cHET 5xFAD n = 10 (M = 3, F = 7), RISP-cKO 5xFAD n = 7 (M = 6, F = 1) (e) 9 months: RISP-cHET CTRL n = 17 (M = 7, F = 10), RISP-cKO CTRL n = 16 (M = 6, F = 10), RISP-cHET 5xFAD n = 23 (M = 10 F = 13), RISP-cKO 5xFAD n = 21 (M = 14, F = 7)). (f) 1 year: RISP-cHET n = 13 (M = 5, F = 8), RISP-cKO n = 10 (M = 3, F = 7), RISP-cHET 5x n = 10 (M = 6, F = 4), RISP-cKO 5xFAD n = 11 (M = 7, F = 4). In a-f we used an RM two-way ANOVA with the Giesser-Greenhouse correction and an uncorrected Fisher’s LSD, with individual variances computed for each comparison. Data represent mean ± s.e.m. black asterisks indicate significant differences between RISP-cHET and RISP-cHET 5xFAD mice, blue asterisks indicate significant differences between RISP-cKO and RISP-cKO 5xFAD mice, crosses indicate significant differents between RISP-cHET 5xFAD and RISP-cKO 5xFAD mice, hashtags indicate significants differences between RISP-cHET and RISP-cKO mice. When compared with specific group indicated *p < 0.05, **p < 0.01, ***p < 0.001.

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Supplementary Table 1

Breakdown of male and female mice in all main figures.

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Stoolman, J.S., Grant, R.A., Poor, T.A. et al. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation. Nat Metab 6, 1492–1504 (2024). https://doi.org/10.1038/s42255-024-01080-1

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