Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells

Shi

Journal of Cell Science

et al. 2016

Mitochondrial morphology is regulated by fusion and fission machinery. Impaired mitochondria dynamics cause various diseases, including Alzheimer's disease. Appoptosin (encoded by SLC25A38) is a mitochondrial carrier protein that is located in the mitochondrial inner membrane. Appoptosin overexpression causes overproduction of reactive oxygen species (ROS) and caspasedependent apoptosis, whereas appoptosin downregulation abolishes β-amyloid-induced mitochondrial fragmentation and neuronal death during Alzheimer's disease. Herein, we found that overexpression of appoptosin resulted in mitochondrial fragmentation in a manner independent of its carrier function, ROS production or caspase activation. Although appoptosin did not affect levels of mitochondrial outer-membrane fusion (MFN1 and MFN2), inner-membrane fusion (OPA1) and fission [DRP1 (also known as DNM1L) and FIS1] proteins, appoptosin interacted with MFN1 and MFN2, as well as with the mitochondrial ubiquitin ligase MITOL (also known as MARCH5) but not OPA1, FIS1 or DRP1. Appoptosin overexpression impaired the interaction between MFN1 and MFN2, and mitochondrial fusion. By contrast, co-expression of MFN1, MITOL and a dominant-negative form of DRP1, DRP1K38A , partially rescued appoptosin-induced mitochondrial fragmentation and apoptosis, whereas co-expression of FIS1 aggravated appoptosin-induced apoptosis. Together, our results demonstrate that appoptosin can interact with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.

Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology

Shi

Journal of Cell Science

et al. 2016

Biological & Pharmaceutical Bulletin

“…18) In hepatocellular carcinoma (HCC) studies, overexpression of the Mfn2 gene resulted in tumor cell apoptosis via mitochondrial pathways. 48,49) Thus, Mfn2 may act as anti-apoptotic regulator during cell responses in vitro and in vivo. 50) In particular, Mfn2 mutations are associated with a plenty of diseases, including cancer, 49) obesity, 17,51) diabetes 52) and liver diseases.…”

Section: Discussionmentioning

confidence: 99%

“…48,49) Thus, Mfn2 may act as anti-apoptotic regulator during cell responses in vitro and in vivo. 50) In particular, Mfn2 mutations are associated with a plenty of diseases, including cancer, 49) obesity, 17,51) diabetes 52) and liver diseases. Sebastián et al 53) showed that liver specific Mfn2 knockout mice led to perturbation of metabolic homeostasis including intolerance and enhanced hepatic gluconeogenesis.…”

Section: Discussionmentioning

confidence: 99%

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FPinduced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/ Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

Seminars in Cancer Biology

“…Interestingly, the oncogenic MAPK/ERK pathway, which is a driver of cancer progression in different tumors, is able to upregulate Drp1 activity in different cancers [147,148] by phosphorylation on serine residue Ser616 [147]. In several human cancers, a poor survival rate is associated with an increased Drp1 level [54,67,70,71,144,149] or a decreased Mfn-2 [150,151] or Mfn-1 amounts [144,152], as also confirmed by the emerging Bioinformatics databases displaying the expression levels of different mitochondria-shaping proteins in human tumors (see The Human Atlas Project [153] and Table 1 for details).…”

Section: Mitochondrial Dynamics As Possible Therapeutic Targetsmentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.