• 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.

• Journal of the Korean Institute of Oriental Medical Informatics
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• v.21 no.1
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• pp.14-22
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• 2015

Flavonoids show diverse bioactivities, such as anti-oxidant, anti-cancer, anti-allergic, anti-inflammatory, and anti-viral. Quercetin is one of the flavonoids present in a wide range of plants, especially onions and consumed all over the world. Recently, it is known that quercetin induces mitochondrial biogenesis in vivo and in vitro. However, detail mechanism of these actions remains unknown. We investigated quercetin's effects on mitochondrial biogenesis in HepG2 cells, and determined the mechanisms involved. We found that quercetin treatment induced the expression of mitochondrial biogenesis activators, $PGC-1{\alpha}$, NRF-1, TFAM, and mitochondrial proteins, cytochorome c and complex IV (COXIV). Moreover, amount of mitochondrial DNA was also increased by quercetin. Quercetin has been known to induce heme oxygenase (HO)-1 in several types of cells. Here, we found quercetin induces HO-1, and inhibition of HO-1 or CO, which is product of HO-1, decreased quercetin-induced mitochondrial biogenesis such as induction of $PGC-1{\alpha}$, NRF-1, TFAM, cytochorome c, COXIV, and mitochondrial DNA. These findings imply that quercetin can increase mitochondrial biogenesis via HO-1/CO system. High glucose results in dysfunction of mitochondria biogenesis. In the present study, 25 mM glucose decreased mitochondrial biogenesis and this damage was restored by quercetin. Conversely, inhibition of HO-1 or CO inhibited quercetin-induced mitochondrial biogenesis rescue. These results suggest that quercetin enhances mitochondrial biogenesis via HO-1/CO system and hence, can rescue mitochondria from damage by high glucose.

• Journal of Radiation Protection and Research
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• v.36 no.3
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• pp.119-126
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• 2011

Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging, and contributes to harmful effects in cultured cells and animal tissues. mtDNA biogenesis genes (NRF-1, TFAM) are essential for the maintenance of mtDNA, as well as the transcription and replication of mitochondrial genomes. Considering that oxidative stress is known to affect mitochondrial biogenesis, we hypothesized that ionizing radiation (IR)-induced reactive oxygen species (ROS) causes mtDNA deletion by modulating the mitochondrial biogenesis, thereby leading to cellular senescence. Therefore, we examined the effects of IR on ROS levels, cellular senescence, mitochondrial biogenesis, and mtDNA deletion in IMR-90 human lung fibroblast cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated at 4 or 8 Gy. Old cells at PD55, and H2O2-treated young cells at PD 39, were compared as a positive control. The IR increased the intracellular ROS level, senescence-associated ${\beta}$-galactosidase (SA-${\beta}$-gal) activity, and mtDNA common deletion (4977 bp), and it decreased the mRNA expression of NRF-1 and TFAM in IMR-90 cells. Similar results were also observed in old cells (PD 55) and $H_2O_2$-treated young cells. To confirm that a increase in ROS level is essential for mtDNA deletion and changes of mitochondrial biogenesis in irradiated cells, the effects of N-acetylcysteine (NAC) were examined. In irradiated and $H_2O_2$-treated cells, 5 mM NAC significantly attenuated the increases of ROS, mtDNA deletion, and SA-${\beta}$-gal activity, and recovered from decreased expressions of NRF-1 and TFAM mRNA. These results suggest that ROS is a key cause of IR-induced mtDNA deletion, and the suppression of the mitochondrial biogenesis gene may mediate this process.

• BMB Reports
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• v.56 no.2
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• pp.84-89
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• 2023

The implications of nutrient starvation due to aging on the degeneration of the retinal pigment epithelium (RPE) is yet to be fully explored. We examined the involvement of AMPK activation in mitochondrial homeostasis and its relationship with the maintenance of a healthy mitochondrial population and epithelial characteristics of RPE cells under nutrient starvation. Nutrient starvation induced mitochondrial senescence, which led to the accumulation of reactive oxygen species (ROS) in RPE cells. As nutrient starvation persisted, RPE cells underwent pathological epithelial-mesenchymal transition (EMT) via the upregulation of TWIST1, a transcription regulator which is activated by ROS-induced NF-κB signaling. Enhanced activation of AMPK with metformin decelerated mitochondrial senescence and EMT progression through mitochondrial biogenesis, primed by activation of PGC1-α. Thus, by facilitating mitochondrial biogenesis, AMPK protects RPE cells from the loss of epithelial integrity due to the accumulation of ROS in senescent mitochondria under nutrient starvation.

• Korean Journal of Exercise Nutrition
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• v.23 no.1
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• pp.7-12
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• 2019

[Purpose] The purpose of the study was to determine the combined effects of resveratrol supplementation with high-flow LSS on mitochondrial biogenesis in human vascular endothelial cells. [Methods] Cultured human umbilical vein endothelial cells were treated with 20 μM of RSV. For the shear experiments, cells grown to a >90% confluence were exposed to physiological levels of LSS (5 to 20 dyne/cm2) for 12 to 36 hours using a cone and plate shear apparatus. Gene expressions were analyzed by western blotting. [Results] Depletion of mitochondrial integrity was directly associated with increase in endothelial activation/dysfunction. The expressions of mitochondrial biogenesis regulator genes, such as SIRT1, PGC-1α, and TFAM, and the mitochondrial contents were significantly increased after treatment with both resveratrol and high-flow LSS for 12 hours. However, supplementation of resveratrol to high-flow LSS for a prolonged duration had no synergistic effect on the levels of mitochondrial biogenesis regulator gene expressions and mitochondrial content compared to the LSS treatment alone. [Conclusion] The present study demonstrated that the supplementation of resveratrol to high-flow LSS has no synergistic effects on enhancing mitochondrial integrity in human vascular endothelial cells.

• Journal of Life Science
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• v.27 no.3
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• pp.361-369
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• 2017

Mitochondrial homeostasis is tightly regulated by two major processes: mitochondrial biogenesis and mitochondrial degradation by autophagy (mitophagy). Research in mitochondrial biogenesis in skeletal muscle in response to endurance exercise training has been well established, while the mechanisms regulating mitophagy and the relationship between mitochondrial biogenesis and degradation following endurance exercise training are not yet well defined. Studies have demonstrated that endurance exercise training increases the expression levels of mitochondrial biogenesis-, dynamics-, mitophagy-related genes in skeletal muscle. However, the increased levels of mitochondrial biogenesis marker proteins such as Cox IV and citrate synthase, by endurance exercise training were abolished when autophagy/mitophagy was inhibited in skeletal muscle. This suggests that both autophagy/mitophagy plays an important role in mitochondrial biogenesis/homeostasis and the coordination between the opposing processes may be important for skeletal muscle adaptation to endurance exercise training to improve metabolic function and endurance exercise performance. It is considered that endurance exercise training regulates each of these processes, mitochondrial biogenesis, fusion and fission events and autophagy/mitophagy, ensuring a relatively constant mitochondrial population. Exercise training may also have contributed to mitochondrial quality control which replaces old and/or unhealthy mitochondria with new and/or healthy ones in skeletal muscle. In this review paper, the molecular mechanisms regulating mitochondrial biogenesis and mitophagy and the coordination between the opposing processes is involved in the cellular adaptation to endurance exercise training in skeletal muscle will be discussed.

• The Journal of the Korea Contents Association
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• v.9 no.4
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• pp.355-363
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• 2009

Increased oxidative stress by abnormal mitochondrial function can damage cell signal transduction and gene expression, and induce insulin resistance or diabetes. Autophagy, however, improve insulin resistance by clearance of malfunctioning mitochondria. Exercise also recovers the muscle dysfunction and degeneration by activating mitochondrial biogenesis. As it seems that exercise and autophagy might act as an orchestrated network to induce mitochondrial biogenesis, we investigated whether autophagy is involved in AMPK signal pathway stimulated by exercise or AICAR to increase mitochondrial biogenesis. And it showed that PGC-1 and mtTFA, but not autophagy marker LC3 mRNA expression were significantly increased by 6 hr of acute exercise. On the other hand, PGC-1 and mtTFA mRNA expression were upregulated by AICAR treatment to C2C12 myotube. However these genes were not inhibited by LC3 siRNA transfection. These results provide the evidence that autopahgy affects on mitochondrial biogenesis through different signal pathway from AMPK signal transduction.

• Molecules and Cells
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• v.39 no.2
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• pp.87-95
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• 2016

Sirt1 is the most prominent and extensively studied member of sirtuins, the family of mammalian class III histone deacetylases heavily implicated in health span and longevity. Although primarily a nuclear protein, Sirt1's deacetylation of Peroxisome proliferator-activated receptor Gamma Coactivator-$1{\alpha}$ (PGC-$1{\alpha}$) has been extensively implicated in metabolic control and mitochondrial biogenesis, which was proposed to partially underlie Sirt1's role in caloric restriction and impacts on longevity. The notion of Sirt1's regulation of PGC-$1{\alpha}$ activity and its role in mitochondrial biogenesis has, however, been controversial. Interestingly, Sirt1 also appears to be important for the turnover of defective mitochondria by mitophagy. I discuss here evidences for Sirt1's regulation of mitochondrial biogenesis and turnover, in relation to PGC-$1{\alpha}$ deacetylation and various aspects of cellular physiology and disease.

• Nutrition Research and Practice
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• v.16 no.2
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• pp.147-160
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• 2022

BACKGROUND/OBJECTIVES: Patients with chronic kidney disease (CKD) have a high concentration of uremic toxins in their blood and often experience muscle atrophy. Indoxyl sulfate (IS) is a uremic toxin produced by tryptophan metabolism. Although an elevated IS level may induce muscle dysfunction, the effect of IS on physiological concentration has not been elucidated. Additionally, the effects of ursolic acid (UA) on muscle hypertrophy have been reported in healthy models; however, it is unclear whether UA ameliorates muscle dysfunction associated with chronic diseases, such as CKD. Thus, this study aimed to investigate whether UA can improve the IS-induced impairment of mitochondrial biogenesis. MATERIALS/METHODS: C2C12 cells were incubated with or without IS (0.1 mM) and UA (1 or 2 μM) to elucidate the physiological effect of UA on CKD-related mitochondrial dysfunction and its related mechanisms using real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: IS suppressed the expression of differentiation marker genes without decreasing cell viability. IS decreased the mitochondrial DNA copy number and ATP levels by downregulating the genes pertaining to mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Sirt1, and Mef2c), fusion (Mfn1 and Mfn2), oxidative phosphorylation (Cycs and Atp5b), and fatty acid oxidation (Pdk4, Acadm, Cpt1b, and Cd36). Furthermore, IS increased the intracellular mRNA and secretory protein levels of interleukin (IL)-6. Finally, UA ameliorated the IS-induced impairment in C2C12 cells. CONCLUSIONS: Our results indicated that UA improves the IS-induced impairment of mitochondrial biogenesis by affecting differentiation, ATP levels, and IL-6 secretion in C2C12 cells. Therefore, UA could be a novel therapeutic agent for CKD-induced muscle dysfunction.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.408-417
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• 2022

Background: Korean Red Ginseng extract (KRGE) has been used as a health supplement and herbal medicine. Astrocytes are one of the key cells in the central nervous system (CNS) and have bioenergetic potential as they stimulate mitochondrial biogenesis. They play a critical role in connecting the brain vasculature and nerves in the CNS. Methods: Brain samples from KRGE-administered mice were tested using immunohistochemistry. Treatment of human brain astrocytes with KRGE was subjected to assays such as proliferation, cytotoxicity, Mitotracker, ATP production, and O₂ consumption rate as well as western blotting to demonstrate the expression of proteins related to mitochondria functions. The expression of hypoxia-inducible factor-1α (HIF-1α) was diminished utilizing siRNA transfection. Results: Brain samples from KRGE-administered mice harbored an increased number of GFAP-expressing astrocytes. KRGE triggered the proliferation of astrocytes in vitro. Enhanced mitochondrial biogenesis induced by KRGE was detected using Mitotracker staining, ATP production, and O₂ consumption rate assays. The expression of proteins related to mitochondrial electron transport was increased in KRGE-treated astrocytes. These effects were blocked by HIF-1α knockdown. The factors secreted from KRGE-treated astrocytes were determined, revealing the expression of various cytokines and growth factors, especially those related to angiogenesis and neurogenesis. KRGE-treated astrocyte conditioned media enhanced the differentiation of adult neural stem cells into mature neurons, increasing the migration of endothelial cells, and these effects were reduced in the background of HIF-1α knockdown. Conclusion: Our findings suggest that KRGE exhibits prophylactic potential by stimulating astrocyte mitochondrial biogenesis through HIF-1α, resulting in improved neurovascular function.