RETRACTED: Abnormal Mitochondria-Endoplasmic Reticulum Communication Promotes Myocardial Infarction

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.

Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury

“…During hypoxia-reoxygenation Fis1 stimulates SR-Ca 2+ release through interaction with BAP31, which, in turn, promotes Bax and Bak translocation to the mitochondria and the initiation of apoptosis ( Lu et al, 2010 ). In agreement with these studies, a recent article by Cheng et al, has shown that loss of the Fis-BAP31 crosstalk protects hearts from myocardial infarction by downregulating mitochondrial ROS production and c-Jun N-terminal kinase (JNK) pathway activation, thus inhibiting cardiomyocyte cell death ( Cheng et al, 2021 ).…”

The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells

“…As reported, artificial induction of MERCs only affected hepatocytes when animals developed obesity, leading to the conclusion that an increased number of MERCs and overweight cause the mitochondrial dysfunction that affects liver metabolism (Arruda et al, 2014). However, these results encountered some dissidence, because another study indicated that increased MERCs improves liver function (Tubbs et al, 2014), as it has been described in other tissues (Gutiérrez et al, 2014;Dia et al, 2020;Cheng et al, 2021). This discrepancy could be explained by several reasons: 1.…”

“…As already mentioned, the loss of interaction between the ER and mitochondria in cardiomyocytes increases with aging and heart disease, thereby decreasing mitochondrial function and altering cellular processes such as oxidative stress, autophagy and metabolic imbalance, consequently affecting the overall heart function (Murley and Nunnari, 2016;Gude et al, 2018). For instance, alterations in the ER-mitochondria interaction result in the progression of acute myocardial ischemia/reperfusion (I/R) (Cheng et al, 2021) and diabetic heart disease (Dia et al, 2020;Zhang et al, 2021a), due to ER and mitochondria stress, which ultimately decrease mitochondrial function (Gude et al, 2018). Mitochondrial Ca 2+ uptake is decreased in aged cardiomyocytes, and this has been associated with a decreased production of NADPH and increased generation of mitochondrial ROS.…”

Mitochondrial Dynamics and Mitophagy in Cardiometabolic Disease

“…BAP31, an ER protein, regulates intracellular calcium homeostasis and ER stress (90). Cheng et al (91) found that silencing Fis1/ BAP31 reduced mitochondrial fission and inhibited JNK activation, which led to a reduction in ROS and promoted cardiomyocyte survival.…”