Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion

Abstract

Sestrin2 (Sesn2) is a stress-inducible protein that declines with aging in the heart. We reported that rescue Sesn2 levels in aged mouse hearts through gene therapy improves the resistance of aged hearts to ischemia and reperfusion (I/R) insults. We hypothesize that Sesn2 as a scaffold protein maintains mitochondrial integrity to protect heart from ischemic injury during I/R. Young C57BL/6 J (3–6 months), aged C57BL/6 J (24–26 months), and young Sesn2 KO (3–6 months, C57BL/6 J background) mice were subjected to in vivo regional ischemia and reperfusion. The left ventricle was collected for transcriptomics, proteomics and metabolomics analysis. The results demonstrated that Sesn2 deficiency leads to aging-like cardiac diastolic dysfunction and intolerance to ischemia reperfusion stress. Seahorse analysis demonstrated that Sesn2 deficiency in aged and young Sesn2 KO versus young hearts lead to impaired mitochondrial respiration rate with defects in Complex I and Complex II activity. The Sesn2 targeted proteomics analysis revealed that Sesn2 plays a critical role in maintaining mitochondrial functional integrity through modulating mitochondria biosynthesis and assembling of oxidative phosphorylation (OXPHOS) complexes. The RNA-Seq data showed that alterations in the expression of mitochondrial compositional and functional genes and substrate metabolism related genes in young Sesn2 KO and aged versus young hearts. Further immunofluorescence and immunoprecipitation analysis demonstrated that Sesn2 is translocated into mitochondria and interacts with OXPHOS components to maintain mitochondrial integrity in response to I/R stress. Biochemical analysis revealed that Sesn2 is associated with citrate cycle components to modulate pyruvate dehydrogenase and isocitrate dehydrogenase activities during I/R stress. Thus, Sesn2 serves as a scaffold protein interacting with OXPHOS components to maintain mitochondrial integrity under I/R stress. Age-related downregulation of cardiac Sesn2 fragilizes mitochondrial functional integrity in response to ischemic stress.

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

“…Interestingly, Sestrin2 also prevented Ca 2+induced mitochondrial permeability transition and restored membrane potential during myocardial IRI [88,89]. Sestrin2-mediated upregulation and activation of Nrf2 plays a pivotal role in attenuating oxidative stress in myocardial IRI [88,89]. Consistently, Nrf2 inhibition causes myocardial IRI to deteriorate [88].…”

“…These inflammatory cytokines, especially IL17, can cause a reinforcement cycle of the inflammatory response inhibited by Sestrin2 (Figure 1) [87]. Interestingly, Sestrin2 also prevented Ca 2+induced mitochondrial permeability transition and restored membrane potential during myocardial IRI [88,89]. Sestrin2-mediated upregulation and activation of Nrf2 plays a pivotal role in attenuating oxidative stress in myocardial IRI [88,89].…”

“…Increased expression of Ucp1 and TFAM can vigorously alleviate myocardial IRI [96,98]. Interestingly, it was revealed that Sestrin2 is necessary for the competent function of oxidative phosphorylation of mitochondrial complexes under physiologic condition or I/R stress [89]. In the absence of Sestrin2, mitochondrial complexes and the Krebs cycle cannot effectively produce ATP 5 Oxidative Medicine and Cellular Longevity [89].…”

“…Interestingly, it was revealed that Sestrin2 is necessary for the competent function of oxidative phosphorylation of mitochondrial complexes under physiologic condition or I/R stress [89]. In the absence of Sestrin2, mitochondrial complexes and the Krebs cycle cannot effectively produce ATP 5 Oxidative Medicine and Cellular Longevity [89]. Increased expression of Sestrin2 during myocardial IRI is a compensatory mechanism to improve mitochondrial function and mitigate myocardial injury [89].…”

“…In the absence of Sestrin2, mitochondrial complexes and the Krebs cycle cannot effectively produce ATP 5 Oxidative Medicine and Cellular Longevity [89]. Increased expression of Sestrin2 during myocardial IRI is a compensatory mechanism to improve mitochondrial function and mitigate myocardial injury [89].…”