• BMB Reports
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• v.54 no.11
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• pp.575-580
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• 2021

Cisplatin is widely known as an anti-cancer drug. However, the effects of cisplatin on mitochondrial function and autophagy-related proteins levels in the skeletal muscle are unclear. The purpose of this study was to investigate the effect of different doses of cisplatin on mitochondrial function and autophagy-related protein levels in the skeletal muscle of rats. Eight-week-old male Wistar rats (n = 24) were assigned to one of three groups; the first group was administered a saline placebo (CON, n = 10), and the second and third groups were given 0.1 mg/kg body weight (BW) (n = 6), and 0.5 mg/kg BW (n = 8) of cisplatin, respectively. The group that had been administered 0.5 mg cisplatin exhibited a reduced BW, skeletal muscle tissue weight, and mitochondrial function and upregulated levels of autophagy-related proteins, including LC3II, Beclin 1, and BNIP3. Moreover, this group had a high LC3 II/I ratio in the skeletal muscle; i.e., the administration of a high dose of cisplatin decreased the muscle mass and mitochondrial function and increased the levels of autophagy-related proteins. These results, thus, suggest that reducing mitochondrial dysfunction and autophagy pathways may be important for preventing skeletal muscle atrophy following cisplatin administration.

• Biomolecules & Therapeutics
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• v.18 no.3
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• pp.235-245
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• 2010

Mitochondria have long been recognized as ATP engines for the cell and recently as a dynamic and mobile organelles that control cell death and life. This exquisite organelle is the site of reactive oxygen species production and is highly vulnerable to exogenous stresses, resulting in catastrophic damage to the cell. Mitochondrial dysfunction is linked to a wide range of age-associated degenerative diseases, such as metabolic syndrome, cardiovascular disease, and neurodegenerative diseases. Understanding the molecular mechanisms of mitochondria-dependent pathogenesis may provide important strategies to treat these diseases. Indeed, mitochondria are emerging therapeutic targets for the mitochondria-related diseases. In this paper, we review the recent concepts of mitochondrial biology and how mitochondria are involved in age-associated degenerative diseases. Furthermore, we summarize the therapeutics which target to improve mitochondrial functions.

• Biomolecules & Therapeutics
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• v.30 no.5
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• pp.399-408
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• 2022

Diabetic cardiomyopathy (DCM) is described as abnormalities of myocardial structure and function in diabetic patients without other well-established cardiovascular factors. Although multiple pathological mechanisms involving in this unique myocardial disorder, mitochondrial dysfunction may play an important role in its development of DCM. Recently, considerable progresses have suggested that mitochondrial biogenesis is a tightly controlled process initiating mitochondrial generation and maintaining mitochondrial function, appears to be associated with DCM. Nonetheless, an outlook on the mechanisms and clinical relevance of dysfunction in mitochondrial biogenesis among patients with DCM is not completely understood. In this review, hence, we will summarize the role of mitochondrial biogenesis dysfunction in the development of DCM, especially the molecular underlying mechanism concerning the signaling pathways beyond the stimulation and inhibition of mitochondrial biogenesis. Additionally, the evaluations and potential therapeutic strategies regarding mitochondrial biogenesis dysfunction in DCM is also presented.

• Biomolecules & Therapeutics
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• v.16 no.1
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• pp.1-8
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• 2008

Mitochondria are important sensor of apoptosis. $H_2O_2-induced$ cell death rate was enhanced by serum deprivation. In this study, we investigated whether serum deprivation using 0.5 or 3 % FBS induces apoptotic cell death through mitochondrial enzyme activation as compared to 10 % FBS. Apoptotic cell death was observed by chromosome condensation and the increase of sub-G0/G1 population. Serum deprivation reduced cell growth rate, which was confirmed by the decrease of S-phase population in cell cycle. Serum deprivation significantly increased caspase-9 activity and cytochrome c release from mitochondria into cytosol. Serum deprivation-induced mitochondrial changes were also indicated by the increase of ROS production and the activation of mitochondrial enzyme, succinate dehydrogenase. Mitochondrial enzyme activity increased by serum deprivation was reduced by the treatment with rotenone, mitochondrial electron transport inhibitor. In conclusion, serum deprivation induced mitochondrial apoptotic cell death through the elevation of mitochondrial changes such as ROS production, cytochrome c release and caspase-9 activation. It suggests that drug sensitivity could be enhanced by the increase of mitochondrial enzyme activity in serum-deprived condition.

• BMB Reports
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• v.57 no.1
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• pp.19-29
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• 2024

Mitochondrial DNA (mtDNA), a multicopy genome found in mitochondria, is crucial for oxidative phosphorylation. Mutations in mtDNA can lead to severe mitochondrial dysfunction in tissues and organs with high energy demand. MtDNA mutations are closely associated with mitochondrial and age-related disease. To better understand the functional role of mtDNA and work toward developing therapeutics, it is essential to advance technology that is capable of manipulating the mitochondrial genome. This review discusses ongoing efforts in mitochondrial genome editing with mtDNA nucleases and base editors, including the tools, delivery strategies, and applications. Future advances in mitochondrial genome editing to address challenges regarding their efficiency and specificity can achieve the promise of therapeutic genome editing.

• Proceedings of the Korean Nuclear Society Conference
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• 2005.10a
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• pp.870-871
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• 2005

• BMB Reports
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• v.45 no.1
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• pp.1-6
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• 2012

Hsp90 is one of the most conserved molecular chaperones ubiquitously expressed in normal cells and over-expressed in cancer cells. A pool of Hsp90 was found in cancer mitochondria and the expression of the mitochondrial Hsp90 homolog, TRAP1, was also elevated in many cancers. The mitochondrial pool of chaperones plays important roles in regulating mitochondrial integrity, protecting against oxidative stress, and inhibiting cell death. Pharmacological inactivation of the chaperones induced mitochondrial dysfunction and concomitant cell death selectively in cancer cells, suggesting they can be target proteins for the development of cancer therapeutics. Several drug candidates targeting TRAP1 and Hsp90 in the mitochondria have been developed and have shown strong cytotoxic activity in many cancers, but not in normal cells in vitro and in vivo. In this review, recent developments in the study of mitochondrial chaperones and the mitochondria-targeted chaperone inhibitors are discussed.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.2
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• pp.167-175
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• 2021

Far-infrared rays (FIR) are known to have various effects on atoms and molecular structures within cells owing to their radiation and vibration frequencies. The present study examined the effects of FIR on gene expression related to glucose transport through microarray analysis in rat skeletal muscle cells, as well as on mitochondrial biogenesis, at high and low glucose conditions. FIR were emitted from a bio-active material coated fabric (BMCF). L6 cells were treated with 30% BMCF for 24 h in medium containing 25 or 5.5 mM glucose, and changes in the expression of glucose transporter genes were determined. The expression of GLUT3 (Slc2a3) increased 2.0-fold (p < 0.05) under 5.5 mM glucose and 30% BMCF. In addition, mitochondrial oxygen consumption and membrane potential (ΔΨm) increased 1.5- and 3.4-fold (p < 0.05 and p < 0.001), respectively, but no significant change in expression of Pgc-1a, a regulator of mitochondrial biogenesis, was observed in 24 h. To analyze the relationship between GLUT3 expression and mitochondrial biogenesis under FIR, GLUT3 was down-modulated by siRNA for 72 h. As a result, the ΔΨm of the GLUT3 siRNA-treated cells increased 3.0-fold (p < 0.001), whereas that of the control group increased 4.6-fold (p < 0.001). Moreover, Pgc-1a expression increased upon 30% BMCF treatment for 72 h; an effect that was more pronounced in the presence of GLUT3. These results suggest that FIR may hold therapeutic potential for improving glucose metabolism and mitochondrial function in metabolic diseases associated with insufficient glucose supply, such as type 2 diabetes.

• Biomolecules & Therapeutics
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• v.19 no.4
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• pp.445-450
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• 2011

Preciously, we demonstrated that a novel NHE-1 inhibitor, KR-33028 attenuated cortical neuronal apoptosis induced by glutamate. In the present study, we investigated the signaling mechanism of neuroprotective effect of KR-33028 against glutamate-induced neuronal apoptosis, especially focusing on mitochondrial death pathway. Our data showed that glutamate induces a biphasic rise in mitochondrial $Ca^{2+}$ and that KR-33028 significantly prevents the second phase increase, but not the first phase increase in mitochondrial $Ca^{2+}$. Furthermore, KR-33028 restored the ${\Delta}{\Psi}_m$ dissipation and cytochrome c release into cytoplasm induced by glutamate in a concentration-dependent manner. The inhibition of mitochondrial $Ca^{2+}$ overload by ruthenium red also inhibited glutamate-induced apoptotic cell death, mitochondrial membrane potential, ${\Delta}{\Psi}_m$ dissipation and cytochrome c release. These data suggest that inhibition of mitochondrial $Ca^{2+}$ overload is likely to be attributable to anti-apoptotic effect of KR-33028. Taken together, our results suggest that anti-apoptotic effects of NHE-1 inhibitor, KR-33028 may be mediated through maintenance of mitochondrial function.

• Biomolecules & Therapeutics
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• v.12 no.1
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• pp.9-18
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• 2004

Opening of the mitochondrial permeability transition pore has been recognized to be involved in cell death. The present study investigated the effect of ${\beta}$-carbolines (harmaline and harmalol) and deprenyl on the dopamine-induced change in the mitochondrial membrane permeability and cell death in differentiated PC12 cells. Cell death due to 250 4{\mu}$M dopamine was inhibited by caspase inhibitors (z-IETD.fmk, z-LEHD.fmk and z-DQMD.fmk) and antioxidants (N-acetylcysteine, ascorbate, superoxide dismutase, catalase and carboxy-PTIO). ${\beta}$-Carbolines prevented the dopamine-induced cell death in PCl2 cells, while deprenyl did not inhibit cell death. ${\beta}$-Carbolines decreased the condensation and fragmentation of nuclei caused by dopamine in PC12 cells. ${\beta}$-Carbolines inhibited the decrease in mitochondrial transmembrane potential, cytochrome c release, formation of reactive oxygen species and depletion of GSH caused by dopamine in PC12 cells, whereas deprenyl did not decrease dopamine-induced mitochondrial damage. ${\beta}$-Carbolines, deprenyl and antioxidants depressed the formation of nitric oxide and melanin in dopamine-treated PC12 cells. The results suggest that cell death due to dopamine PC12 cells is mediated by caspase-8, -9 and -3. Unlike deprenyl, ${\beta}$-carbolines may attenuate the dopamineinduced cell death in PC12 cells by suppressing change in the mitochondrial membrane permeability through inhibition of the toxic action of reactive oxygen and nitrogen species.