• BMB Reports
• /
• 제53권1호
• /
• 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.

• 한국발생생물학회지:발생과생식
• /
• 제21권4호
• /
• 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.

• Molecules and Cells
• /
• 제40권4호
• /
• 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.

• BMB Reports
• /
• 제55권3호
• /
• pp.136-141
• /
• 2022

Inflammation is one of the body's natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could significantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses.

• Journal of Ginseng Research
• /
• 제47권5호
• /
• 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.

• Journal of Animal Science and Technology
• /
• 제63권4호
• /
• pp.766-777
• /
• 2021

Bezafibrate, a fibrate drug used as a lipid-lowering agent to treat hyperlipidemia, is a pan-agonist of peroxisome proliferator-activated receptor alpha. It can enhance mitochondrial fatty acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis. After ovulation, oocytes may get arrested at the metaphase II (MII) stage until fertilization beyond optimal timing, which is termed as post-ovulatory aging. Post-ovulatory aging is a disease that degrades DNA, mitochondria, and oxidative system, and has a negative impact on embryo development and quality; however, the impact of bezafibrate during post-ovulatory aging has not been fully defined. In the present study, we assessed the ability of bezafibrate to prevent the progression of aging in in vitro conditions as well as the underlying mechanisms in pigs. An appropriate concentration of this drug (50 µM) was added, and then oxidative stress, reactive oxygen species downstream, mitochondrial biogenesis, and mitochondrial function were analyzed via immunofluorescence staining and real-time polymerase chain reaction. Bezafibrate significantly alleviated reactive oxygen species and ameliorated glutathione production simultaneously in oocytes and embryos. Moreover, it diminished H2A.X and attenuated CASPASE 3 expression produced by oxidative stress in oocytes and embryos. Furthermore, bezafibrate remarkably improved the mitochondrial function and blastocyst quality as well as markedly reduced the mitochondria/TOM20 ratio and mtDNA copy number. The elevated PARKIN level indicated that mitophagy was induced by bezafibrate treatment after post-ovulatory aging. Collectively, these results suggest that bezafibrate beneficially affects against porcine post-ovulatory oocyte aging in porcine by its antioxidant property and mitochondrial protection.

• 대한유전성대사질환학회지
• /
• 제24권1호
• /
• pp.1-9
• /
• 2024

MELAS 증후군은 다양한 임상 증상을 나타내는 복잡하고 다면적인 미토콘드리아 질환으로, 반복적인 뇌졸중 유사 에피소드, 발작, 당뇨병, 심근병증 등을 포함한다. 이러한 증상들은 뇌, 심장, 근육과 같은 대사적으로 활발한 조직에 미토콘드리아 기능 장애가 미치는 심각한 영향을 반영한다. 현재의 치료는 이러한 증상을 완화하고 미토콘드리아 기능을 개선하는 데 중점을 두고 있으며, 증상 치료, 고용량 비타민 요법 및 고용량 타우린 보충과 같은 혁신적인 접근 방식을 포함한다. 유전자 치료 및 미토콘드리아 표적 약물 분야의 새로운 치료법은 근본적인 유전자 돌연변이를 해결하고 미토콘드리아 건강을 향상시킬 수 있는 유망한 새로운 길을 제공한다. MELAS에 대한 이해가 계속 깊어짐에 따라, 유전자 검사 및 치료적 개입의 발전은 환자의 결과를 크게 개선할 가능성을 갖고 있다. MELAS 치료의 미래는 낙관적이며, 진행 중인 연구는 더 효과적이고 표적화된 치료법을 위한 길을 열어 이 질환의 부담을 줄이고 영향을 받는 개인들의 삶의 질을 향상시키는 것을 목표로 하고 있다.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 2008년도 Proceedings of the Convention
• /
• pp.49-52
• /
• 2008

Parkinson's disease is characterized by motor disturbances and dopaminergic neurodegeneration. parkin and PINK1, two most critical Parkinson's disease-associated genes, have been intensively studied to address the underlying molecular pathogenesis of the disease, but our understanding still remains unclear. Through generation and characterization of Drosophila mutants for PINK1, we show that PINK1 is required for mitochondrial integrity and function in both indirect flight muscles and dopaminergic neurons. Surprisingly, we find that PINK1 mutants share striking phenotypic similarities with parkin mutants. Indeed, transgenic expression of parkin dramatically ameliorates all PINK1 loss-of-function phenotypes, but not vice versa, implicating that Parkin acts downstream of PINK1 in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons. With the establishment of the PINK1-Parkin pathway, we are trying to further investigate the detailed molecular relationship between PINK1 and Parkin using both mammalian dopaminergic neuronal cells for biochemical analysis and Drosophila model animal for genetic analysis. We believe that elucidating the molecular function of Parkinson's disease-associated genes will be of big help for the ultimate understanding of the pathogenic mechanism of this disease and also for the development of effective drugs for Parkinson's disease.

• BMB Reports
• /
• 제53권2호
• /
• pp.100-105
• /
• 2020

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague-Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorie-restricted (18R group), and 11 were both calorie- and protein-restricted with the low-protein diet (6R group). Overnight-fasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state.

• Journal of Microbiology and Biotechnology
• /
• 제29권4호
• /
• pp.538-547
• /
• 2019

The aim of the present study was to evaluate the effects of two well-known natural antioxidants, vitamin C (VC) and vitamin E (VE), on the antifungal activity of honokiol against Candida albicans. The broth microdilution method was employed to test the antifungal activities of honokiol with or without antioxidants in the medium against C. albicans strain. Intracellular reactive oxygen species and lipid peroxidation were determined by fluorescence staining assay. Mitochondrial dysfunction was assessed by detecting the mitochondrial DNA and the mitochondrial membrane potential. We observed that VC could significantly potentiate the antifungal activities of honokiol while VE reduced the effectiveness of honokiol against C. albicans. In addition, VC accelerated honokiol-induced mitochondrial dysfunction and inhibited glycolysis leading to a decrease in cellular ATP. However, VE could protect against mitochondrial membrane lipid peroxidation and rescue mitochondrial function after honokiol treatment. Our research provides new insight into the understanding of the action mechanism of honokiol and VC combination against C. albicans.