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. 2024 Aug;11(31):e2304687.
doi: 10.1002/advs.202304687. Epub 2024 Jun 18.

Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2

Xin Zhong  1 , Shiqiang Gong  1   2 , Linghui Meng  3 , Weifan Yao  1   2 , Ke Du  1 , Linchi Jiao  1 , Guowei Ma  1 , Jingwei Liang  1 , Binbin Wei  1 , Xin Jin  1 , Junhui Tong  1 , Jianru Dong  1 , Mengyu Liu  1 , Menglin Gao  1 , Huachao Jia  1 , Wenjuan Jiang  4 , Zhihua Yu  5 , Yanzhe Wang  4 , Xiaohong Sun  6 , Minjie Wei  1   2 , Mingyan Liu  1
Affiliations

Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2

Xin Zhong et al. Adv Sci (Weinh). 2024 Aug.

Abstract

The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG-M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG-M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC-MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH-mediated OXPHOS pathway, thereby inducing MG-M2 polarization, promoting neuronal survival and exerting an anti-AD role is elucidated.

Keywords: HKII; PDK2; cordycepin; metabolic reprogramming; microglial polarization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
COR treatment restores mitochondrial homeostasis of activated microglia to ameliorate learning and memory deficits in APP/PS1 mice.
Figure 2
Figure 2
COR improves the neuronal micro‐environment by inducing a shift in microglial polarization from the M1‐like to M2‐like phenotype rather than exerting direct neuroprotective effects.
Figure 3
Figure 3
Both OXPHOS and glycolysis are upregulated to maintain mitochondrial homeostasis in AD microglia following COR treatment.
Figure 4
Figure 4
COR elicits neuroprotective efficacy via inducing microglial M2 polarization initiated by mitochondrial metabolic reprogramming.
Figure 5
Figure 5
COR specifically targets HKII and PDK2 within the mitochondria of MG to regulate mitochondrial metabolism.
Figure 6
Figure 6
COR enhances mitochondrial glycolysis to induce microglial M2 polarization by targeting HKII, thereby promoting neuronal survival.
Figure 7
Figure 7
COR treatment promotes OXPHOS by targeting PDK2, inducing microglial M2 polarization and neuronal survival.
Figure 8
Figure 8
COR drove microglial M2 polarization coupled with mitochondrial metabolic reprogramming by dual‐targeting HKII and PDK2 to exert an anti‐AD effect.
See this image and copyright information in PMC

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