Data reported by the World Health Organization in 2018 showed that 5.1% of the global burden of diseases and 5.3% of deaths were attributed to alcohol abuse [1]. Alcoholic liver disease (ALD) caused by excessive alcohol consumption is a major kind of alcohol-related chronic disease, alcoholics present early with reversible hepatic steatosis that further develop into steatohepatitis, liver fibrosis, cirrhosis and liver cancer [2]. However, once it progresses to the terminal stage, there is currently no effective treatment other than liver transplantation.

The pathogenesis of ALD is intricate and multiple mechanisms coexist [3]. Mitochondria are the main target organelles of alcohol metabolism, and the dysfunction is crucial in the development of ALD [4]. In the livers of rats fed with alcohol for 3, 6, or 16 weeks (hepatic steatosis, necrosis, and fibrosis models were established, respectively), mitochondrial glutathione levels were progressively decreased with disease severity [5]. These results suggested that mitochondrial damage is associated with the progression of alcoholic liver injury. Mitochondrial reactive oxygen species (ROS) inducer antimycin A exacerbated alcohol-induced increase in mitochondrial ROS and inhibition of cell viability in rat primary hepatocytes [6]. Conversely, mitochondria-targeted antioxidant mitoquinone ameliorated the increase in oxidative stress, inflammation, and lipid accumulation in the liver of chronic alcohol-fed mice [7]. Hao et al found that specific overexpression of mitochondrial transcription factor A in mouse hepatocytes reduced mitochondrial dysfunction and liver injury induced by chronic alcohol feeding [8]. Thus, mitochondrial damage is not only an early key event in ALD, but also an important target for alcohol-mediated toxicity. However, the mediated mechanism of mitochondrial damage in ALD remains unclear. Therefore, further study is expected to provide the potential theoretical and experimental basis for the early prevention and treatment of ALD.

Frataxin, encoded by the nuclear gene FXN and targeted to the mitochondria, functions in the iron-sulfur cluster (ISC) assembly and heme synthesis [9, 10]. Specifically, in addition to the iron donor, frataxin acts as an allosteric regulator of ISC assembly to bind to the ISCU-NFS1-ISD11-ACP complex and in turn stimulates NFS1 activity [11, 12]. Studies showed that knockout of hepatic FXN in mice led to early mitochondriopathy, such as deposition of mitochondrial dense deposits [13], blocked respiration and reduced activity of ISC-containing proteins [14], and even premature death [15, 16]. Further analysis of livers with FXN knockdown revealed an early impairment of ISC-dependent activity followed by a significant increase in mitochondrial iron level [17]. Previous research by our group found frataxin expression in the liver was reduced, which may be related to lipid deposition induced by a high-fat diet and ferroptosis caused by alcohol treatment [18, 19]. At present, the molecular mechanism of alcoholic liver mitochondrial damage is still unknown. Whether frataxin mediates alcohol-induced liver mitochondrial function warrants further investigation.

Notably, numerous studies have indicated that frataxin expression is highly sensitive to iron level. In yeast lacking the mitochondrial ABC transporter Atm1 (Atm1 deficiency shows features of mitochondrial iron overload and cytoplasmic iron deficiency [20]), frataxin mRNA level was decreased. In fibroblasts and lymphoblasts from Friedreich's ataxia (FRDA) patients and normal controls, deferoxamine (DFO) down-regulated frataxin mRNA and protein expression. Conversely, ammonium ferric citrate (FAC) increased frataxin expression [21]. In the pathogenesis of ALD, one of the core mechanisms is iron overload. Liver tissue from patients with ALD exhibited the accumulation of iron [22]. Furthermore, DFO mitigated the decrease of mitochondrial membrane potential caused by alcohol feeding. While iron chloride (FeCl3) exacerbated mitochondrial dysfunction in alcohol-treated mouse primary hepatocytes [23]. Previous research by our group demonstrated that alcohol exposure and high-fat feeding inhibited frataxin protein expression in mice livers [18, 19]. So, how does frataxin mediate mitochondrial damage in ALD and is it dependent on iron regulation? And whether frataxin protein regulation provides a new perspective for the prevention and treatment of ALD. These questions still need further exploration.

Quercetin is a plant flavonoid compound widely found in daily fruits and vegetables [24, 25]. In addition to its antioxidant effects, numerous studies have shown the roles of quercetin in iron homeostasis. Quercetin ameliorated alcohol-induced hepatic iron overload [26]. Further, Lesjak et al indicated that methylated quercetin at 3-hydroxy decreased the increase of apical intestinal uptake and the inhibition of basolateral iron release compared to quercetin, suggesting that quercetin may regulate iron transport by chelating iron [27]. Mitochondria are central to iron metabolism and iron utilization. Our group has previously shown that quercetin ameliorated alcohol-induced hepatic mitochondrial dysfunction [28]. However, the mechanism by which quercetin protects against mitochondrial damage in ALD and whether iron metabolism is involved in remains to be elucidated. Li et al found that iron chelator deferiprone (DFP) and natural polyphenol resveratrol increased frataxin protein expression in lymphoblasts and fibroblasts of FRDA patients [29]. Furthermore, quercetin alleviated hepatic steatosis by enhancing frataxin-mediated mitophagy in non-alcoholic fatty liver disease [18]. These studies further support the hypothesis that quercetin protects mitochondrial function through regulating frataxin expression in ALD. Given that frataxin plays an essential role in maintaining mitochondrial function and is susceptible to iron level, may quercetin protect mitochondria through iron-frataxin? This warrants further research and disclosure.