RETRACTED ARTICLE: Sirtuin 3 inhibition induces mitochondrial stress in tongue cancer by targeting mitochondrial fission and the JNK-Fis1 biological axis

Abstract

Sirtuin 3 (Sirt3)-modified mitochondrial fission participates in the progression of several types of cancers. However, its role in tongue cancer requires investigation. The aim of our study is to determine whether Sirt3 knockdown regulates the viability of tongue cancer cells via modulating mitochondrial fission. Two types of tongue cancer cells were used in the present study, and siRNA was transfected into the cells to suppress Sirt3 expression. Mitochondrial function and cell apoptosis were determined via immunofluorescence, Western blotting, ELISA, and qPCR assays. A pathway blocker was applied to verify the role of the JNK-Fis1 signaling pathway in regulation of mitochondrial fission. The present study showed that loss of Sirt3 promoted tongue cancer cell death in a manner dependent on mitochondrial apoptosis. Mitochondrial oxidative stress, energy metabolism disorder, mitochondrial cyt-c liberation, and mitochondrial apoptosis activation were observed after Sirt3 silencing. Furthermore, we demonstrated that Sirt3 knockdown activated mitochondrial stress via triggering Fis1-related mitochondrial fission and that inhibition of Fis1-related mitochondrial fission abrogated the pro-apoptotic effect of Sirt3 knockdown on tongue cancer cells. To this end, we found that Sirt3 modulated Fis1 expression via the c-Jun N-terminal kinases (JNK) signaling pathway and that blockade of the JNK pathway attenuated mitochondrial stress and repressed apoptosis in Sirt3 knockdown cells. Altogether, our results identified a tumor-suppressive role for Sirt3 deficiency in tongue cancer via activation of the JNK-Fis1 axis and subsequent initiation of fatal mitochondrial fission. Given these findings, strategies to repress Sirt3 activity and enhance the JNK-Fis1mitochondrial fission cascade have clinical benefits for patients with tongue cancer.

Mitochondrial Fission Protein 1: Emerging Roles in Organellar Form and Function in Health and Disease

“…JNK signaling is an important mediator of cellular stress responses and apoptosis, including its role in insulin resistance and the development of type II diabetes, which has been reviewed extensively by others ( 299 ). A similar role of JNK signaling in pathologic Fis1 mediated mitochondrial fission has also been observed in tongue cancer as a function of Sirtuin 3 regulation ( 300 ). It does not appear that activation of JNK signaling guarantees Fis1 upregulation in all cases though, as JNK activation led only to increased Mff, not Fis1, in the setting of DUSP1 deficiency post IR ( 301 ).…”

Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis

“…These findings are consistent with data showing that an increase of parkin expression results in mitochondrial fragmentation [36] and is associated with MFN2 ubiquitination [37]. In addition, the increase of FIS1, in cystinotic cell, might be due to Sirt3 protein [38] that was found downregulated in the same cystinotic cell line [8]. OPA1, an inner mitochondrial membrane GTPase protein, has gained attention because it regulates important mitochondrial functions, including the balance between mitochondrial fusion and fission processes, the stability of the mitochondrial respiratory chain complexes, the proapoptotic release of cytochrome c molecules sequestered within the mitochondrial cristae and the maintenance of mitochondrial cristae architecture [39].…”

SIRT3 deficiency increases mitochondrial oxidative stress and promotes migration of retinal pigment epithelial cells

“…Increasing evidence shows that oxidative stress affects initiating and progressing the cell dysfunction, which further contributes to diseases such as hyperlipidemia, diabetes mellitus, and hypertension and that SIRT3 deficiency is associated with excessive mitochondrial ROS levels. 38,39 In the present study, SIRT3 deficiency was linked to an increase in mitochondrial ROS levels. Inhibition of mitochondrial ROS using mitochondria-targeted ROS scavengers SS31 and MitoTEMPO decreased mitochondrial ROS levels and ameliorated RPE cell dysfunction induced by high glucose and PDGF.…”