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Targeting PDK2 rescues stress-induced impaired brain energy metabolism

Molecular Psychiatry (2023)Cite this article

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Abstract

Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.

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Fig. 1: CSDS induced depression-like behaviors in mice, and metabolic profile of CSDS mice and first-episode MDD patients.
Fig. 2: Expression of PDK and phosphorylated PDH in the mouse cortex following CSDS exposure.
Fig. 3: GR regulates PDK2 gene expression by binding to its promoter.
Fig. 4: Silencing PDK2 regulates oxygen consumption rate and ameliorates CORT-induced disturbance of TCA cycle carbon flux.
Fig. 5: PDK inhibition attenuates CSDS-induced depressive behaviors.
Fig. 6: GR-specific or PDK2-specific knockdown in neurons increases PDH activity and blocks CSDS-induced depressive behaviors.

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Acknowledgements

We thank all volunteers, patients, and their families for their contribution in this study.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81602846; No. 82272253), Natural Science Foundation of Shandong Province (No. ZR2021MH145), Taishan Scholar Project of Shandong Province (No. tsqn201812159), China International Medical Foundation (No. Z-2018-35-2002), Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation of Jining Medical University (No. JYHL2021FMS19), and Key Research and Development Projects of Jining City (No. 2021YXNS084).

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  1. These authors contributed equally: Changshui Wang, Changmeng Cui.

Authors and Affiliations

  1. Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, China

    Changshui Wang & Changmeng Cui

  2. Translational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, 272000, China

    Pengfei Xu, Li Zhu & Pei Jiang

  3. Faculty of Science and Engineering, University of Nottingham Ningbo China, Ningbo, 315100, China

    Hongjia Xue

  4. ADFA School of Science, University of New South Wales, Canberra, ACT, Australia

    Beibei Chen

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CW and CC wrote the manuscript. PX and LZ performed the in vitro experiments. CW, CC and HX conducted the in vivo experiments. BC and PJ conducted data analysis. PJ contributed to study conception and edited the manuscript.

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Wang, C., Cui, C., Xu, P. et al. Targeting PDK2 rescues stress-induced impaired brain energy metabolism. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02098-9

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