Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke

Version 1 : Received: 10 August 2021 / Approved: 10 August 2021 / Online: 10 August 2021 (09:51:07 CEST)

How to cite: Sharma, S.; Wang, Q.; Muthumalage, T.; Rahman, I. Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke. Preprints 2021, 2021080220 (doi: 10.20944/preprints202108.0220.v1). Sharma, S.; Wang, Q.; Muthumalage, T.; Rahman, I. Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke. Preprints 2021, 2021080220 (doi: 10.20944/preprints202108.0220.v1).

Abstract

Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

Keywords

MIRO1; mitochondrial dysfunction; cigarette smoke; mitophagy; COPD

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