This study aimed to show the α-l-Hexaguluroic acid hexasodium salt (G6) protective effect against UVA-induced photoaging of human keratinocyte cells. We found that G6 localized to the mitochondria and improved mitochondrial functions. G6 increased respiratory chain complex activities, which led to increased cellular ATP content and NAD + /NADH ratio. Thus, G6 alleviated the oxidative stress state in UVA-irradiated cells. Moreover, G6 can regulate the SIRT1/pGC-1α pathway, which enhanced the cells' viability and mitochondria energy metabolism. Notably, the anti-photoaging potential of G6 was directly associated with the increased level of MMP and SIRT1, which was followed by the upregulation of pGC-1α, D-LOOP, and Mt-TFA, and with the transcriptional activation of NRF1/NRF2. Taking all of the results together, we conclude that G6 could protect HaCaT cells from UVA-induced photo-aging via the regulation of mitochondria energy metabolism and its downstream signaling pathways.Int. J. Mol. Sci. 2020, 21, 1201 2 of 16 breathing, a small fraction of electrons may "leak" from the electron transport chain (ETC), especially from complexes I and III reduce oxygen to form ROS [13]. Other mitochondrial proteins, such as alpha-glycerophosphate dehydrogenase, alpha-ketoglutarate, and pyruvate dehydrogenase, have been shown to play a role in ROS production [14]. The mitochondria are also the only organelle in animal cells that have their own mtDNA, which is located physically close to the mitochondrial respiratory chain (MRC). Moreover, those point mutations and deletions in mtDNA were reported to accumulate more and more in various tissues during aging [15], which might consequently lead to the declined MRC capacity in various tissues, such as the skeletal muscle and liver [16,17]. In addition, the fact that the mitochondrial ETC is the major ROS production site results in mitochondria being the primary target for oxidative damage. Related studies have shown that with age, mitochondria become larger, decrease in the number, accumulate vacuoles, sputum abnormalities, and experience mitochondrial rupture [18,19].More importantly, oxidative damage of protein and mtDNA, accompanied by mtDNA mutations, could result in a decrease in mitochondrial respiratory chain enzyme activities, mitochondrial membrane potential, and ATP production [19]. It has been demonstrated that creatine enhances DNA repair caused by UV-induced stress exposure in skin models [20]. Notably, in human clinical settings, formulations containing creatine, acetyl l-carnitine, and NADH can reduce the appearance of aging [21]. The researchers believe that the repair is due to the increased availability of ATP provided by creatine. Under the pressure of ultraviolet light, cells can use this additional ATP to synthesize the required repair enzymes [20,21].Meanwhile, ultraviolet irradiation can also induce the expression of the ROS production, leading to skin inflammation and downregulation of SIRT1 [22]. It has been reported that an enhancement in sirtuin genes and pGC...