Acrolein-inducing ferroptosis contributes to impaired peripheral neurogenesis in zebrafish

Haozhe Qi; Kejia Kan; Carsten Sticht; Katrin Bennewitz; Shu Li; Xin Qian; Gernot Poschet; Jens Kroll

doi:10.3389/fnins.2022.1044213

Acrolein-inducing ferroptosis contributes to impaired peripheral neurogenesis in zebrafish

Front Neurosci. 2023 Jan 12:16:1044213. doi: 10.3389/fnins.2022.1044213. eCollection 2022.

Authors

Haozhe Qi^{1

2}, Kejia Kan^{2

3}, Carsten Sticht⁴, Katrin Bennewitz¹, Shu Li¹, Xin Qian¹, Gernot Poschet⁵, Jens Kroll¹

Affiliations

¹ Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
² Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁴ The Next-Generation Sequencing (NGS) Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵ Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany.

Abstract

Introduction: Diabetes mellitus (DM) is associated with physiological disorders such as delayed wound healing, diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy (DPN). Over 50% of diabetic patients will develop DPN, characterized by motor dysfunction and impaired sensory nerve function. In a previous study, we have uncovered acrolein (ACR) as an upstream initiator which induced impaired glucose homeostasis and microvascular alterations in zebrafish. Whether ACR has specific effects on peripheral neurogenesis and mediates DPN, is still waiting for clarification.

Methods: To evaluate the function of ACR in peripheral nerve development, in vivo experiments were performed in Tg(hb9:GFP) zebrafish. In addition, a series of rescue experiments, metabolomics assessment, and bioinformatics analysis was performed aimed at identifying the molecular mechanisms behind ACR's function and impaired neurogenesis.

Results: Impaired motor neuron development was confirmed in wild-type embryos treated with external ACR. ACR treated embryos displayed ferroptosis and reduction of several amino acids and increased glutathione (GSH). Furthermore, ferroptosis inducer caused similarly suppressed neurogenesis in zebrafish embryos, while anti-ACR treatment or ferroptosis inhibitor could successfully reverse the detrimental phenotypes of ACR on neurogenesis in zebrafish.

Discussion: Our data indicate that ACR could directly activate ferroptosis and impairs peripheral neurogenesis. The data strongly suggest ACR and activated ferroptosis as inducers and promising therapeutic targets for future DPN studies.

Keywords: acrolein; diabetic peripheral neuropathy; ferroptosis; neurodegeneration; neurogenesis.

Grants and funding

This study was supported by grants from the Deutsche Forschungsgemeinschaft (IRTG 1874/2 DIAMICOM as well as CRC 1118), National Natural Science Foundation of China (82200539), and the Deutsche Forschungsgemeinschaft (grant ZUK 40/2010-3009262) for support regarding UPLC-based metabolite quantification. The funding providers were not involved in the design of the study, the collection, analysis and interpretation of data, or in the writing or submission of this article.