Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production

Poorya Amini,Jean-Marc Nuoffer,André Schaller,Shida Yousefi,Charaf Benarafa,Maria Eugenia Soriano,Darko Stojkov,Andrea Felser,Carolina Courage,Luca Scorrano,Laurent Gelman,Hans-Uwe Simon,Christopher B Jackson

doi:10.1038/s41467-018-05387-y

Abstract

Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Dysfunctional OPA1 mutations cause atrophy of the optic nerve leading to blindness. Here, we show that OPA1 has an important role in the innate immune system. Using conditional knockout mice lacking Opa1 in neutrophils (Opa1N∆), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils. This then causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD+ availability. Additionally, we show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Finally, we show that Opa1N∆ mice exhibit a reduced antibacterial defense capability against Pseudomonas aeruginosa.

Highlights

Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity
There is a dispute in the literature regarding the source of extracellular DNA employed for the formation of neutrophil extracellular traps (NETs) and whether there is a requirement for neutrophil death in NET formation[45]
Since mitochondrial respiration is low in these cells, it has been suggested that neutrophils require mitochondria just for undergoing apoptosis[18]

Summary

Introduction

Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Using conditional knockout mice lacking Opa[1] in neutrophils (Opa1NΔ), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils This causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD+ availability. We show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Neutrophils lacking other members of GTPase dynamin family exhibit no such defect in NET formation, suggesting that the OPA1 effects on neutrophils are a consequence of its role in maintaining the mitochondrial cristae junctions tight and likely to be independent of mitochondrial fusion. The findings presented here provide a significant step forward in understanding OPA1 mitochondrial functions in non-neuronal cells and extend the impact of these functions to the innate immune system

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Results

Conclusion