Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia–reperfusion injury

Bassiouni, Wesam; Valencia, Robert; Mahmud, Zabed; Seubert, John M.; Schulz, Richard

doi:10.1007/s00395-023-00999-y

Cited by 10 publications

(3 citation statements)

References 84 publications

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“…Metabolic dysfunction is a well-documented consequence of cardiac IR injury (see − ). The lack of oxygen and altered calcium homeostasis impact pyruvate and fatty acid oxidation, and oxidative phosphorylation .…”

Section: Discussionmentioning

confidence: 99%

Data-Independent Acquisition Proteomics and N-Terminomics Methods Reveal Alterations in Mitochondrial Function and Metabolism in Ischemic-Reperfused Hearts

Hartley,

Bassiouni,

Roczkowsky

et al. 2024

J. Proteome Res.

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Myocardial ischemia-reperfusion (IR) (stunning) injury triggers changes in the proteome and degradome of the heart. Here, we utilize quantitative proteomics and comprehensive degradomics to investigate the molecular mechanisms of IR injury in isolated rat hearts. The control group underwent aerobic perfusion, while the IR injury group underwent 20 min of ischemia and 30 min of reperfusion to induce a stunning injury. As MMP-2 activation has been shown to contribute to myocardial injury, hearts also underwent IR injury with ARP-100, an MMP-2-preferring inhibitor, to dissect the contribution of MMP-2 to IR injury. Using data-independent acquisition (DIA) and mass spectroscopy, we quantified 4468 proteins in ventricular extracts, whereby 447 proteins showed significant alterations among the three groups. We then used subtiligase-mediated N-terminomic labeling to identify more than a hundred specific cleavage sites. Among these protease substrates, 15 were identified following IR injury. We identified alterations in numerous proteins involved in mitochondrial function and metabolism following IR injury. Our findings provide valuable insights into the biochemical mechanisms of myocardial IR injury, suggesting alterations in reactive oxygen/nitrogen species handling and generation, fatty acid metabolism, mitochondrial function and metabolism, and cardiomyocyte contraction.

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Section: Discussionmentioning

confidence: 99%

Data-Independent Acquisition Proteomics and N-Terminomics Methods Reveal Alterations in Mitochondrial Function and Metabolism in Ischemic-Reperfused Hearts

Hartley,

Bassiouni,

Roczkowsky

et al. 2024

J. Proteome Res.

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“…The functional parameters affected by cardioprotective maneuvers include the preservation of respiration and ATP production, the reduction in reactive oxygen species (ROS) release at the onset of reperfusion, the inhibition of mitochondrial permeability transition pore (MPTP) opening at the beginning of reperfusion, the preservation of mitochondrial morphology, and the activation of mitophagy. For details on mitochondrial function in I/R injury, the reader is referred to recent articles [15][16][17][18][19][20]. Taken together, the cardioprotective maneuvers of IPC, RIC, or IPostC target the mitochondria and alter the function of the organelles.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Kinase Signaling for Cardioprotection

Boengler,

Eickelmann,

Kleinbongard

2024

IJMS

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Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.

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“…However, genetic mutation of Mfn2 was shown to interrupt mitochondrial fusion, leading to a neurodegenerative condition [ 40 ]. Following myocardial IR injury, matrix metalloproteinase-2 (MMP-2) activation and cleavage of Mfn2 leads to impaired myocardial contractile function, lowered mitochondrial respiration, and elevated inflammasome response [ 7 ]. MORN repeat-containing protein 4 (MORN4) directly binds to Mfn2 and promotes phosphorylation of Mfn2 at Ser442 by Rho-associated protein kinase 2 (ROCK2) to induce mitochondrial dynamics and mitophagy [ 229 ].…”

Section: Introductionmentioning

confidence: 99%

Mitophagy for cardioprotection

Titus,

Sung,

Zablocki

et al. 2023

Basic Res Cardiol

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Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.

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Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia–reperfusion injury

Cited by 10 publications

References 84 publications

Data-Independent Acquisition Proteomics and N-Terminomics Methods Reveal Alterations in Mitochondrial Function and Metabolism in Ischemic-Reperfused Hearts

Data-Independent Acquisition Proteomics and N-Terminomics Methods Reveal Alterations in Mitochondrial Function and Metabolism in Ischemic-Reperfused Hearts

Mitochondrial Kinase Signaling for Cardioprotection

Mitophagy for cardioprotection

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