Abstract
Myocardial infarction is characterized by cardiomyocyte death, and can be exacerbated by mitochondrial damage and endoplasmic reticulum injury. In the present study, we investigated whether communication between mitochondria and the endoplasmic reticulum contributes to cardiomyocyte death after myocardial infarction. Our data demonstrated that hypoxia treatment (mimicking myocardial infarction) promoted cardiomyocyte death by inducing the c-Jun N-terminal kinase (JNK) pathway. The activation of JNK under hypoxic conditions was dependent on overproduction of mitochondrial reactive oxygen species (mtROS) in cardiomyocytes, and mitochondrial division was identified as the upstream inducer of mtROS overproduction. Silencing mitochondrial division activators, such as B cell receptor associated protein 31 (BAP31) and mitochondrial fission 1 (Fis1), repressed mitochondrial division, thereby inhibiting mtROS overproduction and preventing JNK-induced cardiomyocyte death under hypoxic conditions. These data revealed that a novel death-inducing mechanism involving the BAP31/Fis1/mtROS/JNK axis promotes hypoxia-induced cardiomyocyte damage. Considering that BAP31 is localized within the endoplasmic reticulum and Fis1 is localized in mitochondria, abnormal mitochondria-endoplasmic reticulum communication may be a useful therapeutic target after myocardial infarction.
Highlights
Mitochondria-dependent cardiomyocyte death is one of the primary pathogenic contributors to myocardial infarction (Heusch, 2019; Zhu et al, 2021)
Myocardial infarction is characterized by cardiomyocyte death, but the mechanisms are not fully understood, despite basic and clinical research efforts (Bacmeister et al, 2019; Hofbauer et al, 2019; Behrouzi et al, 2020; Golforoush et al, 2020)
We found that mitochondrial oxidative stress-induced Jun N-terminal kinase (JNK) activation may be the upstream trigger of cardiomyocyte death under hypoxic conditions
Summary
Mitochondria-dependent cardiomyocyte death is one of the primary pathogenic contributors to myocardial infarction (Heusch, 2019; Zhu et al, 2021). Stress-related proteins such as Macrophage stimulating 1 (Wang and Song, 2018), BCL2 interacting protein 3 (Li et al, 2018) and protein kinase C epsilon/delta (Nuñez et al, 2017) have been found to activate the JNK pathway Among these various stimulants, mitochondrial oxidative stress seems to be the main inducer of JNK (Larson-Casey et al, 2020; Seano and Jain, 2020). JNK pathway activation has been associated with increased nuclear factor κB activity, which accelerates mtROS generation by suppressing the mitochondrial respiratory complexes (Mu et al, 2020) This positive feedback between mtROS and JNK amplifies the damage signals to mitochondria and irreversibly impairs their function and structure, creating the early conditions for mitochondria-dependent cell death (Unterleuthner et al, 2020; Watson et al, 2020). In this study, we asked whether interrupting the cooperation between BAP31 and Fis could inhibit mtROS/JNK-induced cardiomyocyte death in order to treat myocardial infarction
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