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Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion
- Source :
- Redox Biology, Redox Biology, Vol 38, Iss, Pp 101824-(2021)
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
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.<br />Graphical abstract Image 1<br />Highlights • Ischemia reperfusion stress triggers Sesn2 accumulation in mitochondria. • Sesn2 interacts with OXPHOS complexes to modulate the adaptive substrate metabolism. • Age-related Sesn2 maintains mitochondrial functional integrity under stress conditions.
- Subjects :
- 0301 basic medicine
Scaffold protein
Aging
Immunoprecipitation
Clinical Biochemistry
Ischemia
Oxidative phosphorylation
Sestrin2
Mitochondrion
AMP-Activated Protein Kinases
Biochemistry
Oxidative Phosphorylation
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
medicine
Animals
lcsh:QH301-705.5
lcsh:R5-920
Chemistry
Organic Chemistry
Nuclear Proteins
Pyruvate dehydrogenase complex
medicine.disease
Cell biology
Mitochondria
Mice, Inbred C57BL
030104 developmental biology
Isocitrate dehydrogenase
Metabolism
lcsh:Biology (General)
Reperfusion
lcsh:Medicine (General)
030217 neurology & neurosurgery
Ischemia reperfusion injury
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....39d62fd49d4f9700d1e2d6ae34b48c17