• Molecules and Cells
• /
• v.39 no.9
• /
• pp.680-686
• /
• 2016

Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins that function to dissipate proton motive force and mitochondrial membrane potential. One UCP has been identified in Caenorhabditis elegans (C. elegans), namely UCP-4. In this study, we examined its expression and localization using a GFP marker in C. elegans. ucp-4 was expressed throughout the body from early embryo to aged adult and UCP-4 was localized in the mitochondria. It is known that increased mitochondrial membrane protential leads to a reactive oxygen species (ROS) increase, which is associated with age-related diseases, including neurodegenerative diseases in humans. A ucp-4 mutant showed increased mitochondrial membrane protential in association with increased neuronal defects during aging, and the neurons of ucp-4 overexpressing animals showed decreased neuronal defects during aging. These results suggest that UCP-4 may be involved in neuroprotection during aging via relieving mitochondrial membrane protential. We also investigated the relationship between UCP-4 and innate immunity because increased ROS can affect innate immunity. ucp-4 mutant displayed increased resistance to the pathogen Staphylococcus aureus compared to wild type. The enhanced immunity in the ucp-4 mutant could be related to increased mitochondrial membrane protential, presumably followed by increased ROS. In summary, UCP-4 might have an important role in neuronal aging and innate immune responses through mediating mitochondrial membrane protential.

• Molecules and Cells
• /
• v.46 no.4
• /
• pp.219-230
• /
• 2023

Down syndrome (DS) is the most common autosomal aneuploidy caused by trisomy of chromosome 21. Previous studies demonstrated that DS affected mitochondrial functions, which may be associated with the abnormal development of the nervous system in patients with DS. Runt-related transcription factor 1 (RUNX1) is an encoding gene located on chromosome 21. It has been reported that RUNX1 may affect cell apoptosis via the mitochondrial pathway. The present study investigated whether RUNX1 plays a critical role in mitochondrial dysfunction in DS and explored the mechanism by which RUNX1 affects mitochondrial functions. Expression of RUNX1 was detected in induced pluripotent stem cells of patients with DS (DS-iPSCs) and normal iPSCs (N-iPSCs), and the mitochondrial functions were investigated in the current study. Subsequently, RUNX1 was overexpressed in N-iPSCs and inhibited in DS-iPSCs. The mitochondrial functions were investigated thoroughly, including reactive oxygen species levels, mitochondrial membrane potential, ATP content, and lysosomal activity. Finally, RNA-sequencing was used to explore the global expression pattern. It was observed that the expression levels of RUNX1 in DS-iPSCs were significantly higher than those in normal controls. Impaired mitochondrial functions were observed in DS-iPSCs. Of note, overexpression of RUNX1 in N-iPSCs resulted in mitochondrial dysfunction, while inhibition of RUNX1 expression could improve the mitochondrial function in DS-iPSCs. Global gene expression analysis indicated that overexpression of RUNX1 may promote the induction of apoptosis in DS-iPSCs by activating the PI3K/Akt signaling pathway. The present findings indicate that abnormal expression of RUNX1 may play a critical role in mitochondrial dysfunction in DS-iPSCs.

• Archives of Pharmacal Research
• /
• v.26 no.11
• /
• pp.951-959
• /
• 2003

A series of typical (chlorpromazine, haloperidol and thioridazine) and atypical (risperidone, quetiapine, clozapine and olanzapine) antipsychotics were tested for effects on integrated bioenergetic functions of isolated rat liver mitochondria. Polarographic measurement of oxygen consumption in freshly isolated mitochondria showed that electron transfer activity at respiratory complex I is inhibited by chlorpromazine, haloperidol, risperidone, and quetiapine, but not by clozapine, olanzapine, or thioridazine. Chlorpromazine and thioridazine act as modest uncouplers of oxidative phosphorylation. The typical neuroleptics inhibited NADH-coenzyme Q reductase in freeze-thawed mitochondria, which is a direct measure of complex I enzyme activity. The inhibition of NADH-coenzyme Q reductase activity by the atypicals risperidone and quetiapine was 2-4 fold less than that for the typical neuroleptics. Clozapine and olanzapine had only slight effects on NADH-coenzyme Q reductase activity, even at 200 $\mu$ M. The relative potencies of these neuroleptic drugs as inhibitors of mitochondrial bioenergetic function is similar to their relative potencies as risk factors in the reported incidence of extrapyramidal symptoms, including tardive dyskinesia (TD). This suggests that compromised bioenergetic function may be involved in the cellular pathology underlying TD.

• Journal of Ginseng Research
• /
• v.46 no.5
• /
• pp.646-656
• /
• 2022

Background: In addition to its use as a health food, ginseng is used in cosmetics and shampoo because of its extensive health benefits. The ginsenoside, Rh2, is a component of ginseng that inhibits tumor cell proliferation and differentiation, promotes insulin secretion, improves insulin sensitivity, and shows antioxidant effects. Methods: The effects of Rh2 on cell survival, extracellular matrix (ECM) protein expression, and cell differentiation were examined. The antioxidant effects of Rh2 in UV-irradiated normal human dermal fibroblast (NHDF) cells were also examined. The effects of Rh2 on mitochondrial function, morphology, and mitophagy were investigated in UV-irradiated NHDF cells. Results: Rh2 treatment promoted the proliferation of NHDF cells. Additionally, Rh2 increased the expression levels of ECM proteins and growth-associated immediate-early genes in ultraviolet (UV)-irradiated NHDF cells. Rh2 also affected antioxidant protein expression and increased total antioxidant capacity. Furthermore, treatment with Rh2 ameliorated the changes in mitochondrial morphology, induced the recovery of mitochondrial function, and inhibited the initiation of mitophagy in UV-irradiated NHDF cells. Conclusion: Rh2 inhibits mitophagy and reinstates mitochondrial ATP production and membrane potential in NHDF cells damaged by UV exposure, leading to the recovery of ECM, cell proliferation, and antioxidant capacity.

• Molecules and Cells
• /
• v.38 no.4
• /
• pp.356-361
• /
• 2015

Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor ${\alpha}$ ($RXR{\alpha}$) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether $RXR{\alpha}$ activation or overexpression can restore IRS1 expression. Both IRS1 and $RXR{\alpha}$ protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of $RXR{\alpha}$ agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. $RXR{\alpha}$ overexpression also increased IRS1 transcription and mitochondrial function. Because $RXR{\alpha}$ overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that $RXR{\alpha}$ directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that $RXR{\alpha}$ bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor ${\delta}$ ($PPAR{\delta}$). These results suggest that $RXR{\alpha}$ overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

• BMB Reports
• /
• v.48 no.10
• /
• pp.539-540
• /
• 2015

It has been proposed that the selective elimination of cancer stem cells (CSCs) using targeted therapy could greatly reduce tumor growth, recurrence, and metastasis. To develop effective therapeutic targets for CSC elimination, we aimed to define the properties of CSC mitochondria, and identify CSC-mitochondria-specific targets in colon cancer. We found that colon CSCs utilize mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. We also found that forkhead box protein 1 (FOXM1)-induced peroxiredoxin 3 (PRDX3) maintains the mitochondrial function, and the FOXM1/PRDX3 mitochondrial pathway maintains survival of colon CSCs. Furthermore, FOXM1 induces CD133 (PROM1/prominin 1) expression, which maintains the stemness of colon CSCs. Together, our findings indicate that FOXM1, PRDX3, and CD133 are potential therapeutic targets for the elimination of CSCs in colon cancer.

• BMB Reports
• /
• v.53 no.1
• /
• pp.47-55
• /
• 2020

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and has become a major socioeconomic issue in many developed countries. Currently available therapeutic agents for AD provide only symptomatic treatments, mainly because the complete mechanism of the AD pathogenesis is still unclear. Although several different hypotheses have been proposed, mitochondrial dysfunction has gathered interest because of its profound effect on brain bioenergetics and neuronal survival in the pathophysiology of AD. Various therapeutic agents targeting the mitochondrial pathways associated with AD have been developed over the past decade. Although most of these agents are still early in the clinical development process, they are used to restore mitochondrial function, which provides an alternative therapeutic strategy that is likely to slow the progression of the disease. In this mini review, we will survey the AD-related mitochondrial pathways and their small-molecule modulators that have therapeutic potential. We will focus on recently reported examples, and also overview the current challenges and future perspectives of ongoing research.

• 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.

• Journal of Nutrition and Health
• /
• v.57 no.1
• /
• pp.53-64
• /
• 2024

Purpose: Mitochondria play a crucial role in preserving skeletal muscle mass, and damage to mitochondria leads to muscle mass loss. This study investigated the effects of oxypeucedanin hydrate, a furanocoumarin isolated from Angelica dahurica radix, on myogenesis and mitochondrial function in vitro and in zebrafish models. Methods: C2C12 myotubes cultured in media containing 0.1, 1, 10, or 100 ng/mL oxypeucedanin hydrate were immunostained with myosin heavy chain (MHC), and then multinucleated MHC-positive cells were counted. The expressions of markers related to muscle differentiation, muscle protein degradation, and mitochondrial function were determined by quantitative reverse transcription polymerase chain reaction. To investigate the effects of oxypeucedanin hydrate on mitochondrial dysfunction, Tg(Xla.Eef1a1:mito-EGFP) zebrafish embryos were treated with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without oxypeucedanin hydrate and analyzed for mito-EGFP intensity and mitochondrial length. Results: Oxypeucedanin hydrate significantly increased MHC-positive multinucleated myotubes (≥ 3 nuclei) and increased the expression of the myogenic marker myosin heavy chain 4. However, it decreased the expressions of muscle-specific RING finger protein 1 and muscle atrophy f-box (markers of muscle protein degradation). Furthermore, oxypeucedanin hydrate enhanced the expressions of markers of mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, transcription factor a mitochondrial, succinate dehydrogenase complex flavoprotein subunit A, and cytochrome c oxidase subunit 1) and mitochondrial fusion (optic atrophy 1). However, it reduced the expression of dynamin-related protein 1 (a mitochondrial fission regulator). Consistently, oxypeucedanin hydrate reduced FOLFIRI-induced mitochondrial dysfunction in the skeletal muscles of zebrafish embryos. Conclusion: The study indicates that oxypeucedanin hydrate promotes myogenesis by improving mitochondrial function, and thus, suggests oxypeucedanin hydrate has potential use as a nutritional supplement that improves muscle mass and function.

• Molecules and Cells
• /
• v.40 no.4
• /
• pp.307-313
• /
• 2017

Caloric restriction (CR) has been shown to extend lifespan and prevent cellular senescence in various species ranging from yeast to humans. Many effects of CR may contribute to extend lifespan. Specifically, CR prevents oxidative damage from reactive oxygen species (ROS) by enhancing mitochondrial function. In this study, we characterized 33 single electron transport chain (ETC) gene-deletion strains to identify CR-induced chronological lifespan (CLS) extension mechanisms. Interestingly, defects in 17 of these 33 ETC gene-deleted strains showed loss of both respiratory function and CR-induced CLS extension. On the contrary, the other 16 respiration-capable mutants showed increased CLS upon CR along with increased mitochondrial membrane potential (MMP) and intracellular adenosine triphosphate (ATP) levels, with decreased mitochondrial superoxide generation. We measured the same parameters in the 17 non-respiratory mutants upon CR. CR simultaneously increased MMP and mitochondrial superoxide generation without altering intracellular ATP levels. In conclusion, respiration is essential for CLS extension by CR and is important for balancing MMP, ROS, and ATP levels.