RAGE availability lessens the degree of dysfunctional mitochondrial bioenergetics following chronic secondhand smoke exposure

The receptor for advanced glycation end products (RAGE) is an immunoglobulin-type receptor abundantly expressed by lung parenchyma that coordinates inflammatory responses. We have previously described roles for RAGE following exposure to tobacco smoke (both primary and secondhand) and environmental diesel particulate matter. While inflammatory signaling, tissue remodeling, and pulmonary function have each been investigated, mitochondrial fitness that may underpin cellular health has not been characterized in a chronic exposure model. The current study assessed mitochondrial bioenergetics in RAGE knock out (RKO) and wild type (WT) mice exposed to 3 months of secondhand smoke (SHS) via a nose-only delivery system (Sireq Scientific, Montreal, Canada) or room air (RA). Select mice were also co-administered SHS and semi-synthetic glycosaminoglycan ethers (SAGEs) that inhibit RAGE/ligand interactions. We discovered that mitochondrial respiration was significantly decreased in WT+SHS mice compared to WT+RA following the addition of glutamate/malate, ADP, succinate, and FCCP. Each of these sequential substrates revealed less severe mitochondrial respiration compromise in RKO +SHS compared to WT+SHS mice, suggesting the absence of RAGE was sufficient to blunt waning mitochondrial fitness. Importantly, mitochondrial respiration was significantly improved in WT+SHS+SAGEs mice compared to WT+SHS mice. These results provide a snapshot of mitochondrial fitness following chronic SHS exposure and suggest a role for RAGE signaling in altering cellular bioenergetics during exposure. This work was supported by funding from the National Institutes of Health (NIH 1R15-HL152257, PRR and JAA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.