Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury

Abstract

Sirtuin-3 (Sirt3) deacetylates several mitochondrial proteins implicated into cerebral ischemia/reperfusion (I/R) injury. The mitochondrial unfolded protein response (UPR mt ) favors mitochondrial proteostasis during various stressors. Here, we used Sirt3 transgenic mice and a transient middle cerebral artery occlusion model to evaluate the molecular basis of Sirt3 on the UPR mt during brain post-ischemic dysfunction. The present study illustrated that Sirt3 abundance was suppressed in the brain after brain ischemic abnormalities. Overexpression of Sirt3 in vivo suppressed the infarction size and attenuated neuroinflammation after brain I/R injury. Sirt3 overexpression restored neural viability by reducing mitochondrial ROS synthesis, maintaining the mitochondrial potential and improving mitochondrial adenosine triphosphate synthesis. Sirt3 overexpression protected neuronal mitochondria against brain post-ischemic malfunction via eliciting the UPR mt by the forkhead box O3 (Foxo3)/sphingosine kinase 1 (Sphk1) pathway. Inhibiting either the UPR mt or the Foxo3/Sphk1 pathway relieved the favorable influence of Sirt3 on neural function and mitochondrial behavior. In contrast, Sphk1 overexpression was sufficient to reduce the infarction size, attenuate neuroinflammation, sustain neuronal viability and prevent mitochondrial abnormalities during brain post-ischemia dysfunction. Thus, the UPR mt protects neural viability and mitochondrial homeostasis, and the Sirt3/Foxo3/Sphk1 pathway is a promosing therapeutic candidate for ischemic stroke.

Gene networks governing the response of a calcareous sponge to future ocean conditions reveal lineage‐specific XBP1 regulation of the unfolded protein response

“…Some histone modifying enzymes, including acetyltransferases ( CBP and ELP ), deacetylases ( SIR2 and SIR6 ), methyltransferases ( KMT2E , SETB1 , and EHMT1 ), and demethylases ( KDM3B and KDM5A ), were classified as hub genes of module L5 (Table S18 ). Homologous genes such as CBP‐1 in worm, SIRT3 in mice, and KDM4B in human have all been shown to regulate the activation of UPR (Li et al., 2021 ; Wang et al., 2018 ; Xiaowei et al., 2023 ).…”

Mitochondrial stress: a key role of neuroinflammation in stroke

“…This implies that ATF5-dependent UPR mt may serve as a regulatory mechanism to dampen the inflammatory response in microglia and potentially mitigate neuroinflammation-associated damage. Xie et al found that the activation of UPR mt attenuated neuroinflammation after ischemic stroke [ 99 ], and in SAH UPR mt regulated the neuronal mitochondrial homeostasis, which decreased the early brain injury [ 100 ].…”

“…Furthermore, dietary intake of n-3 polyunsaturated fatty acids attenuated mitochondrial oxidative stress and increased the mitophagy of astrocytes in the condition of hypoxia to limit A1-specific astrocyte polarization, thereby reducing the production of inflammatory cytokines and neurotoxins, subsequently improving the neurological outcomes of mice with ischemic stroke [ 118 ]. In addition, Sirtuin-3 (Sirt3), a NAD+-dependent deacetylase, was reported to modulate the UPR mt and attenuate neuroinflammation after cerebral ischemia [ 99 ]. Sirt3 is a mitochondrial NAD+-dependent protein deacetylase that regulates the balance of energy metabolism, ROS generation [ 119 ].…”

“…Sirt3 is a mitochondrial NAD+-dependent protein deacetylase that regulates the balance of energy metabolism, ROS generation [ 119 ]. Sirt3 activates the UPR mt by increasing Foxo3a and Sphkl expression, subsequently Sphkl expression relieves neuroinflammation after ischemic stroke [ 99 ]. Thus, activation of UPR mt and mitophagy reveal neuroprotection by mitigate neuroinflammation.…”