Related Experiment Video
Updated: Jun 20, 2025
Real-Time Measurement of the Mitochondrial Bioenergetic Profile of Neutrophils
Published on: June 2, 2023
Mitochondrial perturbations in low-protein-diet-fed mice are associated with altered neutrophil development and
Mehakpreet K Thind1, Emiliano Miraglia2, Catriona Ling3
1Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada; The Childhood Acute Illness & Nutrition Network (CHAIN), Nairobi, Kenya.
Insights
Severe malnutrition impairs neutrophil function, increasing infection risks in children. This study reveals protein deficiency disrupts neutrophil development, leading to increased pathogen spread and lung damage, but nicotinamide may offer a therapeutic solution.
Area of Science:
- Immunology
- Nutritional Science
- Cell Biology
Background:
- Severe malnutrition is linked to increased infections and mortality in young children.
- Neutrophil response dysregulation is suspected in malnutrition-related adverse outcomes, but poorly understood.
Purpose of the Study:
- To investigate the impact of protein deficiency on neutrophil function and development.
- To explore the underlying mechanisms of impaired neutrophil immunity in malnutrition.
- To identify potential nutritional interventions for malnutrition-associated immune deficits.
Main Methods:
- Utilized a lipopolysaccharide-challenged low-protein diet (LPD) mouse model to simulate malnutrition.
- Analyzed neutrophil mitochondrial dynamics and ATP generation.
- Assessed neutrophil differentiation and antimicrobial capabilities.
- Evaluated lung damage and pathogen spread in LPD mice.
Main Results:
- Protein deficiency disrupts neutrophil mitochondrial dynamics and ATP production.
- This disruption obstructs neutrophil differentiation, leading to immature, atypical neutrophils.
- Immature neutrophils exhibit impaired antimicrobial responses, exacerbating pathogen spread and lung damage.
- Nicotinamide treatment boosted neutrophil-mediated immunity in LPD mice.
Conclusions:
- Protein deficiency severely compromises neutrophil development and function, contributing to increased mortality risk in malnutrition.
- Targeting neutrophil mitochondrial health and differentiation presents a potential therapeutic avenue.
- Nicotinamide shows promise as a nutritional strategy to enhance immunity in malnourished individuals.
Abstract:
Severe malnutrition is associated with infections, namely lower respiratory tract infections (LRTIs), diarrhea, and sepsis, and underlies the high risk of morbidity and mortality in children under 5 years of age. Dysregulations in neutrophil responses in the acute phase of infection are speculated to underlie these severe adverse outcomes; however, very little is known about their biology in this context. Here, in a lipopolysaccharide-challenged low-protein diet (LPD) mouse model, as a model of malnutrition, we show that protein deficiency disrupts neutrophil mitochondrial dynamics and ATP generation to obstruct the neutrophil differentiation cascade. This promotes the accumulation of atypical immature neutrophils that are incapable of optimal antimicrobial response and, in turn, exacerbate systemic pathogen spread and the permeability of the alveolocapillary membrane with the resultant lung damage. Thus, this perturbed response may contribute to higher mortality risk in malnutrition. We also offer a nutritional therapeutic strategy, nicotinamide, to boost neutrophil-mediated immunity in LPD-fed mice.
