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Upregulation of MDH1 acetylation by HDAC6 inhibition protects against oxidative stress-derived neuronal apoptosis following intracerebral hemorrhage

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Abstract

Oxidative stress impairs functional recovery after intracerebral hemorrhage (ICH). Histone deacetylase 6 (HDAC6) plays an important role in the initiation of oxidative stress. However, the function of HDAC6 in ICH and the underlying mechanism of action remain elusive. We demonstrated here that HDAC6 knockout mice were resistant to oxidative stress following ICH, as assessed by the MDA and NADPH/NADP+ assays and ROS detection. HDAC6 deficiency also resulted in reduced neuronal apoptosis and lower expression levels of apoptosis-related proteins. Further mechanistic studies showed that HDAC6 bound to malate dehydrogenase 1 (MDH1) and mediated-MDH1 deacetylation on the lysine residues at position 121 and 298. MDH1 acetylation was inhibited in HT22 cells that were challenged with ICH-related damaging agents (Hemin, Hemoglobin, and Thrombin), but increased when HDAC6 was inhibited, suggesting an interplay between HDAC6 and MDH1. The acetylation-mimetic mutant, but not the acetylation-resistant mutant, of MDH1 protected neurons from oxidative injury. Furthermore, HDAC6 inhibition failed to alleviate brain damage after ICH when MDH1 was knockdown. Taken together, our study showed that HDAC6 inhibition protects against brain damage during ICH through MDH1 acetylation.

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Data availability

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

Abbreviations

Bax:

Bcl-2-associated X protein

Caspase-3:

Cysteiny aspartate specific proteinase-3

Co-IP:

Co-immunoprecipitation

IP:

Immunoprecipitation

DMSO:

Dimethyl sulfoxide

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HDACs:

Histone deacetylases

HDAC6:

Histone deacetylases 6

ICH:

Intracerebral hemorrhage

MDH1:

Malate dehydrogenase 1

MDA:

Malondialdehyde

mNSS:

Modified neurological severity score

NAD:

Nicotinamide adenine Dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate

ROS:

Reactive oxygen species

siRNA:

Small interfering RNA

TubA:

Tubastatin A

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Acknowledgements

We are grateful to the members of Dr Cui’s laboratory for their kind suggestions.

Funding

This work was supported by grants from National Natural Science Foundation of China (81571210, 81771282, and 82171305) and Xuzhou Innovation Capacity Building Program (KC19239) to Dr. Guiyun Cui, by grants from the National Natural Science Foundation of China (81971134), the Natural Science Foundation of Jiangsu Province (BK20191152), Medical Scientific Research Project of Jiangsu Provincial Health Commission (ZDB2020017), and Xuzhou Key Research and Development Program (KC19131) to Dr. **nchun Ye, by grants from the National Natural Science Foundation of China (82001276) to Dr. Hu, and by grants from Development Fund of Affiliated Hospital of Xuzhou Medical University (XYFM2020033) to Miao Wang.

Author information

Author notes

  1. Miao Wang and Chao Zhou have contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatrics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu Province, People’s Republic of China

    Miao Wang

  2. Department of Neurology, The Affiliated Jiangning Hospital With Nan**g Medical University, Nan**g, Jiangsu, China

    Delian Kong & Wei**g Ma

  3. Department of Neurology, Xuzhou First People’s Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Miao Wang & Delian Kong

  4. Institute of Nervous System Diseases and Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, No. 99 West Huaihai Road, Xuzhou, 221006, Jiangsu Province, People’s Republic of China

    Chao Zhou, Lu Yu, Bingchen Lv, Yan Wang, Weifeng Wu, Mingyue Zhou & Guiyun Cui

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  1. Miao Wang
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Contributions

GYC and MW: contributed to research design and manuscript writing. MW: executed most experiments. CZ: contributed to data acquirement and analyzation. LY: assisted experiments accomplishment. WJM and BCL: helped with most of the mouse experiments. YW: assisted protein immunoprecipitation. WFW and MYZ: assisted protein extraction and animal experiments. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Miao Wang or Guiyun Cui.

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Authors declare no competing financial interests.

Study approval

All animal experiments carried out were approved by the Jiangsu Provincial Animal Care, and all mice procedures were approved by the institutional Animal Use and Care Committee of XuZhou Medical University.

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Wang, M., Zhou, C., Yu, L. et al. Upregulation of MDH1 acetylation by HDAC6 inhibition protects against oxidative stress-derived neuronal apoptosis following intracerebral hemorrhage. Cell. Mol. Life Sci. 79, 356 (2022). https://doi.org/10.1007/s00018-022-04341-y

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