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Extensive mitochondrial proteome disturbance occurs during the early stages of acute myocardial ischemia.

ABSTRACT: Mitochondrial malfunction leads to the remodeling of myocardial energy metabolism during myocardial ischemia (MI). However, the alterations to the mitochondrial proteome profile during this period has not yet been clarified. An acute MI model was established by high position ligation of the left anterior descending artery in 8-week-old C57BL/6N mice. After 15 min of ligation, the animals were euthanized, and their hearts were collected. The myocardial ultrastructure was observed using transmission electron microscopy (TEM). The cardiac mitochondrial proteome profile was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analyses. TEM showed that the outer membrane of the mitochondria was dissolved, and the inner membrane (cristae) was corrupted and broken down extensively in the MI group. The mitochondrial membrane potential was decreased. More than 1,700 mitochondrial proteins were identified by LC-MS/MS analysis, and 119 were differentially expressed. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis showed that endopeptidase activity regulation, the mitochondrial inner membrane, oxidative phosphorylation, the hypoxia-inducible factor-1 signaling pathway, the pentose phosphate pathway and the peroxisome proliferator-activated receptor signaling pathway were involved in the pathophysiological process in the early stage of acute MI. Extensive and substantial changes in the mitochondrial proteins as well as mitochondrial microstructural damage occur in the early stages of acute MI. In the present study, the series of proteins crucially involved in the pathways of mitochondrial dysfunction and metabolism were identified. Further studies are needed to clarify the roles of these proteins in myocardial metabolism remodeling during acute MI injury.

SUBMITTER: Wang J

PROVIDER: S-EPMC8688935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background： Mitochondria malfunction leads to myocardial energy metabolism remodeling during myocardial ischemia. However, the mitochondrial proteome profile during this period has not been clarified. Methods：Acute myocardial ischemia (MI) model was established by high ligation of left anterior descending (LAD) coronary artery in 8-week-old C57BL/6N mice. After 15 min of ligation, the animals were sacrificed and hearts were collected. Myocardium ultrastructure was observed by transmission electron microscope (TEM). The cardiac mitochondrial proteome profile was analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach and bioinformatics analysis. Results：Observation of TEM showed the mitochondria outer membrane was dissolved, inner membrane (cristae) was corrupted and disappeared extensively in the MI group. The MMP was decreased in the MI group compared with the Sham (p < 0.05). More than 1,700 mitochondrial proteins were screened by LC-MS/MS analysis, and 119 differentially expressed proteins were identified in the MI group (p < 0.05). 27 of the differential proteins were up-regulated and 16 were down-regulated, and the other 76 proteins showed differences between “with or without”. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis showed that endopeptidase activity regulation, mitochondrial inner membrane, oxidative phosphorylation, hypoxia-inducible factor-1 (HIF-1) signal pathway, pentose phosphate pathway, and PPAR signal pathway were involved in the pathophysiological process in the early stage of acute myocardial ischemia. Conclusion：Extensive and significant changes of mitochondrial proteins along with mitochondria microstructure damages arise in the early stage of acute MI. Series of the proteins are crucial in the pathways of mitochondrial dysfunction, positive regulation of mitochondrion autophagy in respiratory, collagen-containing extracellular matrix, and metabolism. Further studies are needed to clarify the roles and details of these proteins in acute MI injury.

Project description:Preserving mitochondrial activity is crucial in rescuing cardiac function following acute myocardial ischemia/reperfusion (I/R). The sex difference in myocardial functional recovery has been observed after I/R. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we aimed to determine the implication of mitochondrial Cx43 in sex-related myocardial responses and to examine the effect of estrogen (17β-estradiol, E2) on Cx43, particularly mitochondrial Cx43-involved cardiac protection following I/R. Mouse primary cardiomyocytes and isolated mouse hearts (from males, females, ovariectomized females, and doxycycline-inducible Tnnt2-controlled Cx43 knockout without or with acute post-ischemic E2 treatment) were subjected to simulated I/R in culture or Langendorff I/R (25-min warm ischemia/40-min reperfusion), respectively. Mitochondrial membrane potential and mitochondrial superoxide production were measured in cardiomyocytes. Myocardial function and infarct size were determined. Cx43 and its isoform, Gja1-20k, were assessed in mitochondria. Immunoelectron microscopy and co-immunoprecipitation were also used to examine mitochondrial Cx43 and its interaction with estrogen receptor-α by E2 in mitochondria, respectively. There were sex disparities in stress-induced cardiomyocyte mitochondrial function. E2 partially restored mitochondrial activity in cardiomyocytes following acute injury. Post-ischemia infusion of E2 improved functional recovery and reduced infarct size with increased Cx43 content and phosphorylation in mitochondria. Ablation of cardiac Cx43 aggravated mitochondrial damage and abolished E2-mediated cardiac protection during I/R. Female mice were more resistant to myocardial I/R than age-matched males with greater protective role of mitochondrial Cx43 in female hearts. Post-ischemic E2 usage augmented mitochondrial Cx43 content and phosphorylation, increased mitochondrial Gja1-20k, and showed cardiac protection.

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Extensive mitochondrial proteome disturbance occurs during the early stages of acute myocardial ischemia.

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