• Journal of Ginseng Research
• /
• v.47 no.5
• /
• pp.615-621
• /
• 2023

Korean Red Ginseng (KRG) plays a key role in heme oxygenase (HO)-1 induction under physical and moderate oxidative stress conditions. The transient and mild induction of HO-1 is beneficial for cell protection, mitochondrial function, regeneration, and intercellular communication. However, chronic HO-1 overexpression is detrimental in severely injured regions. Thus, in a chronic pathological state, diminishing HO-1-mediated ferroptosis is beneficial for a therapeutic approach. The molecular mechanisms by which KRG protects various cell types in the central nervous system have not yet been established, especially in terms of HO-1-mediated mitochondrial functions. Therefore, in this review, we discuss the multiple roles of KRG in the regulation of astrocytic HO-1 under pathophysiological conditions. More specifically, we discuss the role of the KRG-mediated astrocytic HO-1 pathway in regulating mitochondrial functions in acute and chronic neurodegenerative diseases as well as physiological conditions.

• BMB Reports
• /
• v.55 no.11
• /
• pp.528-534
• /
• 2022

Mitochondria are cellular organelles that perform various functions within cells. They are responsible for ATP production, cell-signal regulation, autophagy, and cell apoptosis. Because the mitochondrial proteins that perform these functions need Ca²⁺ ions for their activity, mitochondria have ion channels to selectively uptake Ca²⁺ ions from the cytoplasm. The ion channel known to play the most important role in the Ca²⁺ uptake in mitochondria is the mitochondrial calcium uniporter (MCU) holo-complex located in the inner mitochondrial membrane (IMM). This ion channel complex exists in the form of a complex consisting of the pore-forming protein through which the Ca²⁺ ions are transported into the mitochondrial matrix, and the auxiliary protein involved in regulating the activity of the Ca²⁺ uptake by the MCU holo-complex. Studies of this MCU holo-complex have long been conducted, but we didn't know in detail how mitochondria uptake Ca²⁺ ions through this ion channel complex or how the activity of this ion channel complex is regulated. Recently, the protein structure of the MCU holo-complex was identified, enabling the mechanism of Ca²⁺ uptake and its regulation by the MCU holo-complex to be confirmed. In this review, I will introduce the mechanism of action of the MCU holo-complex at the molecular level based on the Cryo-EM structure of the MCU holo-complex to help understand how mitochondria uptake the necessary Ca²⁺ ions through the MCU holo-complex and how these Ca²⁺ uptake mechanisms are regulated.

• Development and Reproduction
• /
• v.21 no.4
• /
• pp.417-424
• /
• 2017

Alzheimer's disease (AD) is neurodegenerative disease, characterized by the progressive decline of memory, cognitive functions, and changes in personality. The major pathological features in postmortem brains are neurofibrillary tangles and amyloid beta ($A{\beta}$) deposits. The majority of AD cases are sporadic and age-related. Although AD pathogenesis has not been established, aging and declining mitochondrial function has been associated. Mitochondrial dysfunction has been observed in AD patients' brains and AD mice models, and the mice with a genetic defect in mitochondrial complex I showed enhanced $A{\beta}$ level in vivo. To elucidate the role of mitochondrial complex I in AD, we used SH-SY5Y cells transfected with DNA constructs expressing human amyloid precursor protein (APP) or human Swedish APP mutant (APP-swe). The expression of APP-swe increased the level of $A{\beta}$ protein in comparison with control. When complex I was inhibited by rotenone, the increase of ROS level was remarkably higher in the cells overexpressing APP-swe compared to control. The number of dead cell was significantly increased in APP-swe-expressing cells by complex I inhibition. We suggest that complex I dysfunction accelerate amyloid toxicity and mitochondrial complex I dysfunction in aging may contribute to the pathogenesis of sporadic AD.

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

• BMB Reports
• /
• v.31 no.6
• /
• pp.607-610
• /
• 1998

Transcription of mitochondrial DNA in the yeast S. cerevisiae depends on recognition of a consensus nonanucleotide promoter sequence by mitochondrial RNA polymerase specificity factor, which is a 43 kDa polypeptide encoded by the nuclear MTF1 gene. Mtf1p has only limited amino acid sequence homology to bacterial sigma factors, but functions in many ways like sigma in that it is required for promoter recognition and initiation of transcription. To analyze the corebinding region of Mtf1p, monoclonal antibodies to this protein were prepared. Recombinant Mtf1p overproduced in E. coli was purified to near homogeneity and used to raise monoclonal antibodies (mAbs). From fused cells screened for Mtf1p mAbs by immunodot blot analysis, 19 positive clones were initially isolated. Further analysis of positive clones by Western blotting resulted in 4 mAbs of Mtf1p.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 2008.04a
• /
• pp.23-30
• /
• 2008

Mitochondria biogenesis requires a coordination of two genomes, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Disruption of mitochondria function leads to a loss of mitochondrial membrane potential and ATP generating capacity and consequently results in chronic degenerative diseases including insulin resistance, metabolic syndrome and neurodegenerative diseases. Although PPAR-${\gamma}$ coactivator-$1{\alpha}$ (PGC-$1{\alpha}$) was discovered as a central regulator of mitochondria biogenesis and a transcriptional co-activator of nuclear respiratory factor (NRF) and mitochondrial transcription factor A (Tfam), the expressions of PGC-$1{\alpha}$, NRF and Tfam were not significantly altered in tissues showing abnormal mitochondria functions. This observation suggests that there should be another regulator(s) for mitochondria function. Here, we demonstrate microRNAs (miRNAs) can modulate mitochondria function. Overexpression of microRNA dissipated mitochondrial membrane potential and increased ROS production in vitro and in vivo. It will be discussed the target of microRNA and its role in metabolic syndrome.

• Journal of Microbiology and Biotechnology
• /
• v.31 no.6
• /
• pp.875-881
• /
• 2021

The mitochondrial targeting domain (MTD) of Noxa contributes to its mitochondrial localization and to apoptosis induction. As a peptide, MTD fused with octa-arginine (R8), a CPP, induces necrosis related to intracellular calcium influx and destruction of mitochondria and endoplasmic reticulum. We searched for homologs of MTD, and compared their cell killing capability when fused with R8. Three of the seven peptides triggered cell death with similar mechanisms. The comparative analysis of peptide sequences showed that four amino acid sites of MTD are critical in regulating necrosis, suggesting the potential to generate artificial, adjustable cytotoxic peptides, which could be effective medicines for many diseases. Thus, homologs functionality could hint to the functions of their belonging proteins.

• Journal of Ginseng Research
• /
• v.45 no.3
• /
• pp.371-379
• /
• 2021

Mitochondrial dysfunction contributes to the pathogenesis and prognosis of many common disorders, including neurodegeneration, stroke, myocardial infarction, tumor, and metabolic diseases. Ginsenosides, the major bioactive constituents of Panax ginseng (P. ginseng), have been reported to play beneficial roles in the molecular pathophysiology of these diseases by targeting mitochondrial dysfunction. In this review, we first introduce the types of ginsenosides and basic mitochondrial functions. Then, recent findings are summarized on different ginsenosides targeting mitochondria and their key signaling pathways for the treatment of multiple diseases, including neurological disorders, cancer, heart disease, hyperglycemia, and inflammation are summarized. This review may explain the common targets of ginsenosides against multiple diseases and provide new insights into the underlying mechanisms, facilitating research on the clinical application of P. ginseng.

• Journal of Ginseng Research
• /
• v.45 no.4
• /
• pp.473-481
• /
• 2021

Background: Mitochondrial dysfunction is one of the significant reasons for Alzheimer's disease (AD). Ginsenosides, natural molecules extracted from Panax ginseng, have been demonstrated to exert essential neuroprotective functions, which can ascribe to its anti-oxidative effect, enhancing central metabolism and improving mitochondrial function. However, a comprehensive analysis of cellular mitochondrial bioenergetics after ginsenoside treatment under Aβ-oxidative stress is missing. Methods: The antioxidant activities of ginsenoside Rb₁, Rd, Re, Rg₁ were compared by measuring the cell survival and reactive oxygen species (ROS) formation. Next, the protective effects of ginsenosides of mitochondrial bioenergetics were examined by measuring oxygen consumption rate (OCR) in PC12 cells under Aβ-oxidative stress with an extracellular flux analyzer. Meanwhile, mitochondrial membrane potential (MMP) and mitochondrial dynamics were evaluated by confocal laser scanning microscopy. Results: Ginsenoside Rg₁ possessed the strongest anti-oxidative property, and which therefore provided the best protective function to PC12 cells under the Aβ oxidative stress by increasing ATP production to 3 folds, spare capacity to 2 folds, maximal respiration to 2 folds and non-mitochondrial respiration to 1.5 folds, as compared to Aβ cell model. Furthermore, ginsenoside Rg1 enhanced MMP and mitochondrial interconnectivity, and simultaneously reduced mitochondrial circularity. Conclusion: In the present study, these results demonstrated that ginsenoside Rg₁ could be the best natural compound, as compared with other ginsenosides, by modulating the OCR of cultured PC12 cells during oxidative phosphorylation, in regulating MMP and in improving mitochondria dynamics under Aβ-induced oxidative stress.

• The Korean Journal of Physiology and Pharmacology
• /
• v.20 no.2
• /
• pp.201-211
• /
• 2016

Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment ($10{\mu}M$) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-$1{\alpha}$ ($PGC1{\alpha}$) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving $PGC1{\alpha}$ during cardiac HR injuries.