Modulatory effects of S1QEL on OxLDL-induced metabolic alterations and inflammatory responses in human monocytes

Oxidized low-density lipoprotein (OxLDL) plays a key role in initiating monocyte activation, glycolytic reprogramming, and pro-inflammatory cytokine production-processes that contribute to aging and progression of age-related diseases such as atherosclerosis and steatohepatitis. Mitochondrial reactive oxygen species (ROS), particularly from complex I, are known modulators of these responses. This study aimed to evaluate the impact of OxLDL on the metabolic and inflammatory responses of primary human monocytes and determine whether co-treatment with site-1 Qo electron leak (S1QEL), a mitochondrial complex I-specific ROS suppressor, could mitigate these effects.

Monocytes were isolated from healthy human donors and treated with OxLDL alone or in combination with S1QEL. Metabolic parameters including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using the Seahorse XF Analyzer. Pro-inflammatory gene expression (IL1B, CXCL8, IL6, TNF) was assessed using quantitative real-time polymerase chain reaction.

OxLDL treatment significantly increased ECAR, indicating enhanced glycolytic activity, without altering mitochondrial respiration (OCR). This metabolic shift was attenuated by S1QEL co-treatment. OxLDL also upregulated IL1B, CXCL8, and IL6 expression, which was significantly reduced by S1QEL. TNF expression remained unchanged across all conditions.

S1QEL effectively suppresses both glycolytic reprogramming and pro-inflammatory cytokine expression induced by OxLDL in human monocytes. These findings underscore the role of mitochondrial complex I-derived ROS in monocyte activation and highlight S1QEL as a potential therapeutic agent for targeting inflammation in aging and several age-related diseases.