Bothrops lanceolatus snake venom impairs mitochondrial respiration and induces DNA release in human heart preparation

Abstract

Introduction

Envenomations by Bothrops snakebites can induce overwhelming systemic inflammation ultimately leading to multiple organ system failure and death. Release of damage-associated molecular pattern molecules (DAMPs), in particular of mitochondrial origin, has been implicated in the pathophysiology of the deregulated innate immune response.

Objective

To test whether whole Bothrops lanceolatus venom would induce mitochondrial dysfunction and DAMPs release in human heart preparations.

Methods

Human atrial trabeculae were obtained during cannulation for cardiopulmonary bypass from patients who were undergoing routine coronary artery bypass surgery. Cardiac fibers were incubated with vehicle and whole Bothrops lanceolatus venom for 24hr before high-resolution respirometry, mitochondrial membrane permeability evaluation and quantification of mitochondrial DNA.

Results

Compared with vehicle, incubation of human cardiac muscle with whole Bothrops lanceolatus venom for 24hr impaired respiratory control ratio and mitochondrial membrane permeability. Levels of mitochondrial DNA increased in the medium of cardiac cell preparation incubated with venom of Bothrops lanceolatus.

Conclusion

Our study suggests that whole venom of Bothrops lanceolatus impairs mitochondrial oxidative phosphorylation capacity and increases mitochondrial membrane permeability. Cardiac mitochondrial dysfunction associated with mitochondrial DAMPs release may alter myocardium function and engage the innate immune response, which may both participate to the cardiotoxicity occurring in patients with severe envenomation.

Author summary

Despite initial symptomatic management and adequate antivenin strategy, highly venomous Bothrops snakebites frequently induce overwhelming inflammation leading to multiple organ system failure and death. We state that recognition of venom-associated molecular patterns and cellular damage-associated molecular pattern molecules (DAMPs) by pattern-recognition receptors will engage inflammation and cell-mediated immune response. Due to endosymbiotic bacterial origin of mitochondria, mitochondrial DAMPs released from injured envenomed tissues are recognized as danger signals and exacerbate the innate inflammatory host response. Hence, mitochondrial DAMPs will engage a vicious circle, which deregulates inflammation via aberrant mitochondrial signaling, impaired mitophagy and disruption of mitochondrial dynamics. Delineating critical factors that elicit mtDAMPs release will generate hypothesis for new treatments.