• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.71-77
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• 2012

Mitochondrial dynamics and distribution is critical for their role in bioenergetics and cell survival. We investigated the consequence of altered fission/fusion on mitochondrial function and motility in INS-1E rat clonal ${\beta}$-cells. Adenoviruses were used to induce doxycycline-dependent expression of wild type (WT-Mfn1) or a dominant negative mitofusin 1 mutant (DN-Mfn1). Mitochondrial morphology and motility were analyzed by monitoring mitochondrially-targeted red fluorescent protein. Adenovirus-driven overexpression of WT-Mfn1 elicited severe aggregation of mitochondria, preventing them from reaching peripheral near plasma membrane areas of the cell. Overexpression of DN-Mfn1 resulted in fragmented mitochondria with widespread cytosolic distribution. WT-Mfn1 overexpression impaired mitochondrial function as glucose- and oligomycin-induced mitochondrial hyperpolarization were markedly reduced. Viability of the INS-1E cells, however, was not affected. Mitochondrial motility was significantly reduced in WT-Mfn1 overexpressing cells. Conversely, fragmented mitochondria in DN-Mfn1 overexpressing cells showed more vigorous movement than mitochondria in control cells. Movement of these mitochondria was also less microtubule-dependent. These results suggest that Mfn1-induced hyperfusion leads to mitochondrial dysfunction and hypomotility, which may explain impaired metabolism-secretion coupling in insulin-releasing cells overexpressing Mfn1.

• IMMUNE NETWORK
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• v.21 no.4
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• pp.30.1-30.12
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• 2021

High expression of mitofusin-2 (MFN2), a mitochondrial fusion protein, has been frequently associated with poor prognosis of patients with cervical cancer. Here, we aimed to identify the function of MFN2 in cervical cancer to understand its influence on disease prognosis. To this end, from cervical adenocarcinoma, we performed an MTT assay and quantitative RT-PCR (qRT-PCR) analysis to assess the effects of MFN2 on the proliferation and of HeLa cells. Then, colony-formation ability and tumorigenesis were evaluated using a tumor xenograft mouse model. The migration ability related to MFN2 was also measured using a wound healing assay. Consequently, epithelial-mesenchymal transition (EMT) of MFN2-knockdowned HeLa cells originating from adenocarcinoma. markers related to MFN2 were assessed by qRT-PCR. Clinical data were analyzed using cBioPortal and The Cancer Genome Atlas. We found that MFN2 knockdown reduced the proliferation, colony formation ability, migration, and in vivo tumorigenesis of HeLa cells. Primarily, migration of MFN2-knockdowned HeLa cells decreased through the suppression of EMT. Thus, we concluded that MFN2 facilitates cancer progression and in vivo tumorigenesis in HeLa cells. These findings suggest that MFN2 could be a novel target to regulate the EMT program and tumorigenic potential in HeLa cells and might serve as a therapeutic target for cervical cancer. Taken together, this study is expected to contribute to the treatment of patients with cervical cancer.

• Annals of Clinical Neurophysiology
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• v.21 no.1
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• pp.57-60
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• 2019

Axonal Charcot-Marie-Tooth disease (CMT2) has most frequently been associated with mutations in the MFN2 gene. MFN2 encodes mitofusin 2, which is a mitochondrial fusion protein that plays an essential role in mitochondrial function. We report CMT2 in a Korean father and his son that manifested with gait difficulties and progressive atrophy of the lower legs. Molecular analysis revealed a novel heterozygous c.2096T>C (p.Leu699Pro) mutation in the exon 18 of MFN2 in both subjects. We suggest that this novel mutation in MFN2 is probably a pathogenic mutation for CMT2.

• International Journal of Oral Biology
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• v.42 no.3
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• pp.85-90
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• 2017

Mitochondria participate in various intracellular metabolic pathways such as generating intracellular ATP, synthesizing several essential molecules, regulating calcium homeostasis, and producing the cell's reactive oxygen species (ROS). Emerging studies have demonstrated newly discovered roles of mitochondria, which participate in the regulation of innate immune responses by modulating NLRP3 inflammasomes. Here, we review the recently proposed pathways to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation: 1) mitochondrial ROS, 2) calcium mobilization, 3) nicotinamide adenine dinucleotide ($NAD^+$) reduction, 4) cardiolipin, 5) mitofusin, 6) mitochondrial DNA, 7) mitochondrial antiviral signaling protein. Furthermore, we highlight the significance of mitophagy as a negative regulator of mitochondrial damage and NLRP3 inflammasome activation, as potentially helpful therapeutic approaches which could potentially address uncontrolled inflammation.

• Toxicological Research
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• v.32 no.1
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• pp.35-46
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• 2016

No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation between sirtuin 1, mitophagy and ischemic liver injury.

• Molecules and Cells
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• v.42 no.12
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• pp.893-905
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• 2019

Mitochondria are highly dynamic organelles that constantly undergo fission and fusion processes that closely related to their function. Disruption of mitochondrial dynamics has been demonstrated in acute kidney injury (AKI), which could eventually result in cell injury and death. Previously, we reported that augmenter of liver regeneration (ALR) alleviates renal tubular epithelial cell injury. Here, we gained further insights into whether the renoprotective roles of ALR are associated with mitochondrial dynamics. Changes in mitochondrial dynamics were examined in experimental models of renal ischemia-reperfusion (IR). In a model of hypoxia-reoxygenation (HR) injury in vitro, dynamin-related protein 1 (Drp1) and mitochondrial fission process protein 1 (MTFP1), two key proteins of mitochondrial fission, were downregulated in the Lv-ALR + HR group. ALR overexpression additionally had an impact on phosphorylation of Drp1 Ser637 during AKI. The inner membrane fusion protein, Optic Atrophy 1 (OPA1), was significantly increased whereas levels of outer membrane fusion proteins Mitofusin-1 and -2 (Mfn1, Mfn2) were not affected in the Lv-ALR + HR group, compared with the control group. Furthermore, the mTOR/4E-BP1 signaling pathway was highly activated in the Lv-ALR + HR group. ALR overexpression led to suppression of HR-induced apoptosis. Our collective findings indicate that ALR gene transfection alleviates mitochondrial injury, possibly through inhibiting fission and promoting fusion of the mitochondrial inner membrane, both of which contribute to reduction of HK-2 cell apoptosis. Additionally, fission processes are potentially mediated by promoting tubular cell survival through activating the mTOR/4E-BP1 signaling pathway.

• Journal of Life Science
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• v.31 no.5
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• pp.464-474
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• 2021

Inflammation induced by metabolic syndromes, cancers, injuries, and sepsis can alter cellular metabolism by reducing mitochondrial function via oxidative stress, thereby resulting in neuropathy and muscle atrophy. In this study, we investigated whether butyrate, a short chain fatty acid produced by gut microbiota, could prevent mitochondrial dysfunction and muscle atrophy induced by lipopolysaccharide (LPS) in the C2C12 cell line. LPS-activated MAPK signaling pathways increased the levels of the mitochondrial fission signal, p-DRP1 (Ser616), and the muscle atrophy marker, atrogin 1. Interestingly, butyrate significantly inhibited the phosphorylation of JNK and p38 and reduced the atrogin 1 level in LPS-treated C2C12 cells while increasing the phosphorylation of DRP1 (Ser637) and levels of mitofusin2, which are both mitochondrial fusion markers. Next, we investigated the effect of MAPK inhibitors, finding that butyrate had the same effect as JNK inhibition in C2C12 cells. Also, butyrate inhibited the LPS-induced expression of pyruvate dehydrogenase kinase 4 (PDK4), resulting in decreased PDHE1α phosphorylation and lactate production, suggesting that butyrate shifted glucose metabolism from aerobic glycolysis to oxidative phosphorylation. Finally, we found that these effects of butyrate on LPS-induced mitochondrial dysfunction were caused by its antioxidant effects. Thus, our findings demonstrate that butyrate prevents LPS-induced muscle atrophy by improving mitochondrial dynamics and metabolic stress via the inhibition of JNK phosphorylation. Consequently, butyrate could be used to improve LPS-induced mitochondrial dysfunction and myopathy in sepsis.