Caffeine Targets SIRT3 to Enhance SOD2 Activity in Mitochondria

Abstract

Caffeine is chemically stable and not readily oxidized under normal physiological conditions but also has antioxidant effects, although the underlying molecular mechanism is not well understood. Superoxide dismutase (SOD) 2 is a manganesecontaining enzyme located in mitochondria that protects cells against oxidative stress by scavenging reactive oxygen species (ROS). SOD2 activity is inhibited through acetylation under conditions of stress such as exposure to ultraviolet (UV) radiation. Sirtuin 3 (SIRT3) is the major mitochondrial nicotinamide adenine dinucleotide (NAD +)-dependent deacetylase, which deacetylates two critical lysine residues (lysine 68 and lysine 122) on SOD2 and promotes its antioxidative activity. In this study, we investigated whether the antioxidant effect of caffeine involves modulation of SOD2 by SIRT3 using in vitro and in vivo models. The results show that caffeine interacts with SIRT3 and promotes direct binding of SIRT3 with its substrate, thereby enhancing its enzymatic activity. Mechanistically, caffeine bound to SIRT3 with high affinity (K D = 6.858 × 10 −7 M); the binding affinity between SIRT3 and its substrate acetylated p53 was also 9.03 (without NAD +) or 6.87 (with NAD +) times higher in the presence of caffeine. Caffeine effectively protected skin cells from UV irradiation-induced oxidative stress. More importantly, caffeine enhanced SIRT3 activity and reduced SOD2 acetylation, thereby leading to increased SOD2 activity, which could be reversed by treatment with the SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) in vitro and in vivo. Taken together, our results show that caffeine targets SIRT3 to enhance SOD2 activity and protect skin cells from UV irradiation-induced oxidative stress. Thus, caffeine, as a small-molecule SIRT3 activator, could be a potential agent to protect human skin against UV radiation.

Caffeine as a Factor Influencing the Functioning of the Human Body—Friend or Foe?

“…Caffeine can also mechanistically facilitate the elimination of ROS by activating autophagy through the inhibition of AR, increasing the level of sirtuin 3 (SIRT3) and the activation of 5′ adenosine monophosphate-activated protein kinase [ 199 ]. Similar investigations were also conducted by Xu et al [ 200 ], and the authors showed that caffeine (4–512 μM) promoted SIRT3 activity and reduced SOD2 (superoxide dismutase 2) acetylation. The results of the above studies show that caffeine targets SIRT3 to enhance SOD2 activity and protect skin cells from UV irradiation-induced oxidative stress.…”

“…The results of the above studies show that caffeine targets SIRT3 to enhance SOD2 activity and protect skin cells from UV irradiation-induced oxidative stress. Thus caffeine, as a small-molecule SIRT3 activator, could be a potential agent to protect human skin against UV radiation [ 200 ].…”

Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats

“…Furthermore, previous studies showed that the upregulation of SIRT3-mediated SOD2 and PRDX3 deacetylation could enhance the mitochondrial antioxidant defense activity and alleviate oxidative damage to the mitochondria [ 71 , 72 ]. Moreover, SIRT3 can promote SOD2 transcription by interacting with the FOXO3 α proteins and activating the FOXO3 α -dependent antioxidant-encoding gene SOD2 [ 73 ]. A similar regulation has been reported between SIRT1 and PRDX3 [ 74 ].…”

The bibenzyl derivatives of Dendrobium officinale prevent UV-B irradiation induced photoaging via SIRT3

“…The accumulation of ROS in HaCaT cells will promote the release of cytochrome C to the cytoplasm, activate the caspase cascade and cause cell apoptosis [ 24 ]. The results showed that UV-B irradiation significantly increased the activation of caspase 3 and caspase 9 and the expression of Bax in the model group, while the antiapoptotic protein Bcl-2 decreased significantly.…”