Novel mitochondrial complex I-inhibiting peptides restrain NADH dehydrogenase activity

Yao-Peng Xue,Mou-Chieh Kao,Chung-Yu Lan

doi:10.1038/s41598-019-50114-2

Yao-Peng Xue, Mou-Chieh Kao + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-50114-2

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Journal: Scientific Reports	Publication Date: Sep 23, 2019
Citations: 15	License type: open-access

Affiliation: National Tsing Hua University

Abstract

The emergence of drug-resistant fungal pathogens is becoming increasingly serious due to overuse of antifungals. Antimicrobial peptides have potent activity against a broad spectrum of pathogens, including fungi, and are considered a potential new class of antifungals. In this study, we examined the activities of the newly designed peptides P-113Du and P-113Tri, together with their parental peptide P-113, against the human fungal pathogen Candida albicans. The results showed that these peptides inhibit mitochondrial complex I, specifically NADH dehydrogenase, of the electron transport chain. Moreover, P-113Du and P-113Tri also block alternative NADH dehydrogenases. Currently, most inhibitors of the mitochondrial complex I are small molecules or artificially-designed antibodies. Here, we demonstrated novel functions of antimicrobial peptides in inhibiting the mitochondrial complex I of C. albicans, providing insight in the development of new antifungal agents.

Highlights

Antimicrobial peptides (AMPs) are found at most sites in the human body and include defensins, histatins, cathelicidins, dermcidins, and hepcidins[2]
We demonstrated that P-113Du and P-113Tri, along with P-113, target C. albicans mitochondria by inhibiting complex I, the NADH dehydrogenase subunit of the complex
Our previous study suggested that the candidacidal activity of P-113Du and P-113Tri may be related to the generation of ROS8

Summary

Introduction

AMPs are found at most sites in the human body and include defensins, histatins, cathelicidins, dermcidins, and hepcidins[2]. This result reflects an overall increased level of intracellular ROS in C. albicans cells with AMP treatment (Fig. 1a and Supplementary Fig. S1a). Between the peptides and mitochondrial complex I of the respiration chain, the respiratory oxygen consumption rate of C. albicans was measured dynamically using an Oxygraph-2k respirometer.

Results

Conclusion