Abstract
Exposure to organic dust (OD) in agriculture is known to cause respiratory symptoms including loss of lung function. OD exposure activates multiple signaling pathways since it contains a variety of microbial products and particulate matter. Previously, we have shown how OD exposure leads to the secretion of HMGB1 and HMGB1-RAGE signaling, and how this can be a possible therapeutic target to reduce inflammation. Cellular mitochondria are indispensable for homeostasis and are emerging targets to curtail inflammation. Recently, we have also observed that OD exposure induces mitochondrial dysfunction characterized by loss of structural integrity and deficits in bioenergetics. However, the role of HMGB1 in OD-induced mitochondrial dysfunction in human bronchial epithelial (NHBE) cells remains elusive. Therefore, we aimed to study whether decreased levels of intracellular HMGB1 or antibody-mediated neutralization of secreted HMGB1 would rescue mitochondrial dysfunction. Single and repeated ODE exposure showed an elongated mitochondrial network and cristolysis whereas HMGB1 neutralization or the lack thereof promotes mitochondrial biogenesis evidenced by increased mitochondrial fragmentation, increased DRP1 expression, decreased MFN2 expression, and increased PGC1α expression. Repeated 5-day ODE exposure significantly downregulated transcripts encoding mitochondrial respiration and metabolism (ATP synthase, NADUF, and UQCR) as well as glucose uptake. This was reversed by the antibody-mediated neutralization of HMGB1. Our results support our hypothesis that, in NHBE cells, neutralization of ODE-induced HMGB1 secretion rescues OD-induced mitochondrial dysfunction.
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Abbreviations
- OD:
-
Organic dust
- ODE:
-
Organic dust extract
- NHBE:
-
Normal human bronchial epithelial
- BEGM:
-
Bronchial epithelial growth medium
- ALI:
-
Air liquid interface
- HMGB1:
-
High mobility group box 1
- RAGE:
-
Receptor for advanced glycation end products
- TLR:
-
Toll-like receptor
- NOD2:
-
Nucleotide-binding oligomerization domain-containing 2
- ATP:
-
Adenosine triphosphate
- OXPHOS:
-
Oxidative phosphorylation
- TFAM:
-
Mitochondrial transcription factor A
- COX:
-
Cytochrome C oxidase
- mtND1:
-
Mitochondrial NADH dehydrogenase 1
- TEM:
-
Transmission electron microscopy
- DMSO:
-
Dimethyl sulfoxide
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Acknowledgements
We would like to thank Tracey Stewart at Iowa State University’s Roy J. Carver High-Resolution Microscopy Facility for assistance with transmission electron microscopy. We would like to thank Dr. Kevin Tracey (Feinstein Institutes for Medical Research, Northwell Health, NY) for providing us with the anti-HMGB1 neutralization antibody and Dr. Y.S. Prakash (Mayo Clinic, Rochester, MN) and Dr. K. L. Bailey (UNMC, Omaha, NE) for providing us with normal human bronchial epithelial cells when needed. We would also like to thank the department of biomedical sciences and Dr. M. Cho at Iowa State University for providing us with access to necessary equipment. We would like to thank Drs. Thippeswamy and Kanthasamy (Biomedical Sciences) for access to equipment and facilities.
Funding
C.C. laboratory is funded through startup grant through Iowa State University, a pilot grant (5 U54 OH007548) from CDC-NIOSH (Centers for Disease Control and Prevention-The National Institute for Occupational Safety and Health) and a seed grant through CVM (College of Veterinary Medicine) at the Iowa State University.
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S.M. Bhat participated in the design of experiments, performed the experiments, analyzed the data, and wrote the manuscript. N. Massey performed organic dust extraction. D. Shrestha assisted in culturing of NHBE cells. L. Karriker collected the organic dust samples and edited the manuscript. T. Jelesijević provided the technical expertise required to perform fluorescent microscopy and participated in editing the manuscript. C. Charavaryamath conceptualized the study, participated in the design of the experiments, performed dust extraction, participated in the interpretation of data, and edited the manuscript. All authors have read and approved the final manuscript.
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Bhat, S.M., Massey, N., Shrestha, D. et al. Transcriptomic and ultrastructural evidence indicate that anti-HMGB1 antibodies rescue organic dust-induced mitochondrial dysfunction. Cell Tissue Res 388, 373–398 (2022). https://doi.org/10.1007/s00441-022-03602-3
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DOI: https://doi.org/10.1007/s00441-022-03602-3