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Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages

Nature Metabolism volume 5, pages 804–820 (2023)Cite this article

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Abstract

Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2–5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.

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Fig. 1: UK5099-suppressed inflammatory cytokine production is concentration dependent.
Fig. 2: UK5099 suppresses oxidative phosphorylation, mitochondrial membrane potential as well as HIF-1α stabilization and its regulation of gene expression.
Fig. 3: UK5099 suppresses inflammatory responses independently of MPC expression.
Fig. 4: Off-target effects of UK5099 on cellular metabolism and HIF-1α stabilization.
Fig. 5: Mpc depletion reduces glucose fuel into the TCA cycle.
Fig. 6: The impacts of Mpc depletion on metabolic reprogramming in LPS-stimulated macrophages.
Fig. 7: Mpc depletion is dispensable for proinflammatory cytokine production in LPS-stimulated macrophages.
Fig. 8: Mpc is not required for inflammatory responses in vivo.

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Data availability

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (GSA) in the National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences, under accession code GSA: CRA009169 (RNA-seq data) and GSA: CRA009183 (single-cell RNA-seq data), which are publicly accessible at https://ngdc.cncb.ac.cn/gsa (refs. 49,50). Other data that support the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant nos. 81970073 and 82170090 to F.W.), the Shanghai Science and Technology Commission (grant nos. 19ZR1441600 and 21Y11901100 to F.W.), the Shanghai Pujiang Program (grant no. 2020PJD051 to F.W.), the Outstanding Clinical Discipline Project of Shanghai Pudong, the Top-level Clinical Discipline Project of Shanghai Pudong (grant no. PWYgf2021-05 to Q.L.) and the Academic Leaders Training Program of Pudong Health and Family Planning Commission of Shanghai (grant no. PWRd2019-02 to F.W.).

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Author notes

  1. These authors contributed equally: Linyu Ran, Song Zhang.

Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

    Linyu Ran, Guosheng Wang, Pei Zhao, Jiaxing Sun, Qiang Li & Feilong Wang

  2. Medical College, Tongji University, Shanghai, China

    Linyu Ran & Pei Zhao

  3. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

    Song Zhang, Ryounghoon Jeon & Joerg Herrmann

  4. Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA

    Song Zhang & Ryounghoon Jeon

  5. Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Jiaqi Zhou & Haiyun Gan

  6. Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (KMEDIhub), Daegu, Republic of Korea

    Ryounghoon Jeon

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Contributions

Conceptualization was the responsibility of F.W. and S.Z. Methodology was the responsibility of F.W., S.Z., R.J., J.Z., H.G. and J.H. Validation was the responsibility of F.W. and S.Z. Investigation was the responsibility of L.R., S.Z., G.W. and P.Z. Writing of the original draft was carried out by F.W. and J.H. Review and editing was carried out by F.W., S.Z., Q.L. and J.H. Supervision was the responsibility of F.W., Q.L. and J.H. Funding acquisition was the responsibility of F.W., Q.L. and J.H.

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Correspondence to Joerg Herrmann or Feilong Wang.

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Nature Metabolism thanks Jan Van den Bossche, Laurent Yvan-Charvet and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Giménez-Cassina, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Conditional knock-out of Mpc1 in myeloid cells.

(a) Cell viability of WT BMDMs after 24 hours stimulation with LPS ± 1 hour pre-treatment with different concentrations of UK5099 (n = 6 biologically independent samples). (b) Gene targeting strategy for Mpc1 depletion in exon 3–5 in a Lyz2-conditional manner. (c) and (d) Expression of Mpc1 and Mpc2 mRNA in Mpc1fl/fl and Mpc1ΔLysM BMDMs (n = 4 biologically independent samples). (e) and (f) Expression of MPC1 and MPC2 protein in Mpc1fl/fl and Mpc1ΔLysM BMDMs. (g) and (h) Expression of Mpc1 and Mpc2 mRNA in Mpc1fl/fl and Mpc1ΔLysM AMs (n = 3 mice). (i) Cell viability of Mpc1fl/fl and Mpc1ΔLysM BMDMs after 24 hours stimulation with LPS ± 1 hour pre-treatment with 100 μM UK5099 (n = 8 biologically independent samples). Data are representative of three independent experiments (a, g, h, i). Data are representative of at least ten independent experiments (c to f). P values were calculated using one-way ANOVA with Fisher’s LSD post hoc analysis (a) or unpaired, two-sided Student’s t-test (c, d, g, h, i). Data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 2 UK5099 suppresses macrophages activation independent of MPC expression in LPS-stimulated macrophages.

(a) Volcano plots of gene expression in Mpc1fl/fl and Mpc1ΔLysM BMDMs with or without pre-treatment with 100 μM UK5099 (Related to Figure 3g–i). (b) Venn diagrams showing overlap of UK5099 (100 μM)-altered genes between Mpc1fl/fl and Mpc1ΔLysM BMDMs with (down panel) or without (up panel) LPS stimulation. (c) Heat map of gene expression in Mpc1fl/fl and Mpc1ΔLysM BMDMs after 4 hours stimulation with LPS ± 1 hour pre-treatment with UK5099 (100 μM). The included genes were those significantly changed by UK5099 treatment in both Mpc1fl/fl and Mpc1ΔLysM BMDMs with or without LPS stimulation (Fold change˃1.5 & q-value˂0.05). (d) Flow cytometry analysis of F4/80 and CD11b expression in BMDMs. (e) UMAP clustering of scRNA-seq from Mpc1fl/fl and Mpc1ΔLysM BMDMs after 4 hours stimulation with LPS ± 1 hour pre-treatment with 100 μM UK5099. (f) UMAP plots of Adgre 1 (F4/80), Itgam (CD11b) and Lyz2 (LysM) expression among pooled samples. (g) Heat map of HIF-1α targeted gene expression of Mpc1fl/fl and Mpc1ΔLysM BMDMs after 4 hours stimulation with LPS ± 1 hour pre-treatment with 100 μM UK5099. (h) Heat map of oxidoreductase activity (GO:0016712) Gene Set in LPS-stimulated Mpc1fl/fl (left panel) and Mpc1ΔLysM (right panel) BMDMs with and without 100 μM UK5099 pre-treatment (Related to Fig. 4q). Data are representative of three independent experiments (d).

Extended Data Fig. 3 Mpc1 depletion reduces pyruvate fueling of the TCA cycle in LPS-stimulated macrophages.

(a) to (e) U-[13C]-Pyruvate labeled TCA cycle metabolites in Mpc1fl/fl and Mpc1ΔLysM BMDMs with or without stimulation by LPS for 2 hours (n = 4 biologically independent samples). (f) to (j) U-[13C]-Pyruvate labeled TCA cycle metabolites m+3 fraction in Mpc1fl/fl and Mpc1ΔLysM BMDMs with or without stimulation by LPS for 2 hours (n = 4 biologically independent samples). Data are representative of two independent experiments (a to j). P values were calculated by two-way ANOVA with Fisher’s LSD post hoc analysis. Data are presented as mean ± s.e.m.

Extended Data Fig. 4 Acute loss of Mpc1 has no impact on proinflammatory cytokines production in LPS-stimulated macrophages.

(a) to (b) Expression of Mpc1 and Mpc2 mRNA in Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs treated with 4-Hydroxytamoxifen for 3 days (n = 3 biologically independent samples). (c) Expression of MPC1 and MPC2 protein in Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs treated with 4-Hydroxytamoxifen for 3 days. (d) to (f) Expression of proinflammatory cytokines mRNA in Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs with or without stimulation by LPS for 4 hours (n = 3 biologically independent samples). (g) to (i) Proinflammatory cytokines secretion of Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs with or without stimulation by LPS for 24 hours (n = 4 biologically independent samples). (j) to (l) Expression of proinflammatory cytokines mRNA in Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs after 4 hours stimulation with LPS ± 1 hour pre-treatment with 100 μM UK5099 (n = 3 biologically independent samples). (m) to (o) Proinflammatory cytokines secretion by Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs after 24 hours stimulation with LPS ± 1 hour pre-treatment with 100 μM UK5099 (n = 4 biologically independent samples). (p) Immunoblot analysis of histone acetylation (H3K9) in Mpc1fl/fl and Mpc1ΔLysM-ERT BMDMs with or without stimulation by LPS for the indicated times. Data are representative of at least five independent experiments (a to c, p). Data are representative of four independent experiments (d to i). Data are representative of three independent experiments (j to o). P values were calculated by two-way ANOVA with Fisher’s LSD post hoc analysis (a, b) or unpaired, two-sided Student’s t-test (d to o). Data are presented as mean ± s.e.m.

Source data

Extended Data Fig. 5 Mpc1 depletion reduces lactate fueling of the TCA cycle.

(a) to (d) U-[13C]-Lactate labeled TCA cycle metabolites in Mpc1fl/fl and Mpc1ΔLysM BMDMs (n = 5 biologically independent samples). (e) Gating strategy for peritoneal macrophages.Data are representative of two independent experiments (a to d). P values were calculated using unpaired, two-sided Student’s t-test. Data are presented as mean ± s.e.m.

Extended Data Table 1 UK5099-binding proteins by proteome microarray assays
Full size table
Extended Data Table 2 List of primer sequences used for gene expression analysis
Full size table

Supplementary information

Source data

Source Data Fig. 1

Unprocessed and uncropped images of western blots. RAW images of Fig. 1n.

Source Data Fig. 2

Unprocessed and uncropped images of western blots. RAW images of Fig. 2e.

Source Data Fig. 4

Unprocessed and uncropped images of western blots. RAW images of Fig. 4o.

Source Data Fig. 7

Unprocessed and uncropped images of western blots. RAW images of Fig. 7g,j,m.

Source Data Extended Data Fig. 1

Unprocessed and uncropped images of western blots. RAW images of Extended Data Fig. 1e,f.

Source Data Extended Data Fig. 4

Unprocessed and uncropped images of western blots. RAW images Extended Data Fig. 4c,p.

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Ran, L., Zhang, S., Wang, G. et al. Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages. Nat Metab 5, 804–820 (2023). https://doi.org/10.1038/s42255-023-00800-3

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