Astaxanthin mitigates ethanol-induced mitochondrial dysfunction and activation of mitochondrial unfolded protein response in Kupffer cells

This study investigates the protective effects of astaxanthin (ASTX), a xanthophyll carotenoid, on ethanol-induced mitochondrial dysfunction in Kupffer cells (KCs), resident macrophages in the liver that play a key role in the pathogenesis of alcohol-related liver disease (ALD). Using immortalized mouse KCs (ImKCs) and primary mouse KCs (PmKCs) as in vitro models, we examined the role of ASTX in modulating the mitochondrial unfolded protein response (UPR ^mt ), a critical defense mechanism against mitochondrial stress. Ethanol significantly increased pro-inflammatory cytokines, such as interleukin (Il)-6 , Il-1b , and tumor necrosis factor ( Tnf ), which ASTX countered. Furthermore, upon ethanol exposure, ASTX significantly decreased the accumulation of cellular and mitochondrial reactive oxygen species and preserved mitochondrial respiratory capacity, mitochondrial biogenesis, and cristae structural integrity. Notably, ASTX inhibited the ethanol-induced mRNA and protein expression of several UPR ^mt -related mitochondrial chaperones and proteases, concomitantly preventing the nuclear translocation of activating transcription factor 5, a key regulator of UPR ^mt . Our findings in both ImKCs and PmKCs were largely consistent regarding inflammatory responses and UPR ^mt gene regulation, underscoring the robust protective role of ASTX across multiple Kupffer cell models. These findings underscore the potential of using ASTX as a therapeutic agent for ALD and other conditions associated with oxidative stress and mitochondrial dysfunction.