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Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control
- Source :
- Redox Biology, Redox Biology, Vol 38, Iss, Pp 101777-(2021)
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- The death of cardiomyocytes either through apoptosis or necroptosis is the pathological feature of cardiac ischemia-reperfusion (I/R) injury. Phosphoglycerate mutase 5 (PGAM5), a mitochondrially-localized serine/threonine-protein phosphatase, functions as a novel inducer of necroptosis. However, intense debate exists regarding the effect of PGAM5 on I/R-related cardiomyocyte death. Using cardiac-specific PGAM5 knockout (PGAM5CKO) mice, we comprehensively investigated the precise contribution and molecular mechanism of PGAM5 in cardiomyocyte death. Our data showed that both PGAM5 transcription and expression were upregulated in reperfused myocardium. Genetic ablation of PGAM5 suppressed I/R-mediated necroptosis but failed to prevent apoptosis activation, a result that went along with improved heart function and decreased inflammation response. Regardless of PGAM5 status, mitophagy-related cell death was not apparent following I/R. Under physiological conditions, PGAM5 overexpression in primary cardiomyocytes was sufficient to induce cardiomyocyte necroptosis rather than apoptosis. At the sub-cellular levels, PGAM5 deficiency increased mitochondrial DNA copy number and transcript levels, normalized mitochondrial respiration, repressed mitochondrial ROS production, and prevented abnormal mPTP opening upon I/R. Molecular investigation demonstrated that PGAM5 deletion interrupted I/R-mediated DrpS637 dephosphorylation but failed to abolish I/R-induce Drp1S616 phosphorylation, resulting in partial inhibition of mitochondrial fission. In addition, declining Mfn2 and OPA1 levels were restored in PGAM5CKO cardiomyocytes following I/R. Nevertheless, PGAM5 depletion did not rescue suppressed mitophagy upon I/R injury. In conclusion, our results provide an insight into the specific role and working mechanism of PGAM5 in driving cardiomyocyte necroptosis through imposing mitochondrial quality control in cardiac I/R injury.
- Subjects :
- 0301 basic medicine
Mitochondrial ROS
Programmed cell death
Mitochondrial quality control
Necroptosis
Clinical Biochemistry
MFN2
Biochemistry
Mitochondrial Dynamics
03 medical and health sciences
Mice
0302 clinical medicine
Cardiac I/R injury
Mitophagy
medicine
Phosphoprotein Phosphatases
Animals
lcsh:QH301-705.5
Mice, Knockout
lcsh:R5-920
Chemistry
Mitochondrial fission
Organic Chemistry
Heart
medicine.disease
Cell biology
Mitochondria
Death
030104 developmental biology
lcsh:Biology (General)
Apoptosis
Reperfusion Injury
lcsh:Medicine (General)
Reperfusion injury
030217 neurology & neurosurgery
Research Paper
PGAM5
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....61f35f621cf593e5658116afce1d31d7