• 제목/요약/키워드: Mitochondrial function

검색결과 302건 처리시간 0.025초

Defective Mitochondrial Function and Motility Due to Mitofusin 1 Overexpression in Insulin Secreting Cells

  • Park, Kyu-Sang;Wiederkehr, Andreas;Wollheim, Claes B.
    • The Korean Journal of Physiology and Pharmacology
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    • 제16권1호
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    • pp.71-77
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    • 2012
  • Mitochondrial dynamics and distribution is critical for their role in bioenergetics and cell survival. We investigated the consequence of altered fission/fusion on mitochondrial function and motility in INS-1E rat clonal ${\beta}$-cells. Adenoviruses were used to induce doxycycline-dependent expression of wild type (WT-Mfn1) or a dominant negative mitofusin 1 mutant (DN-Mfn1). Mitochondrial morphology and motility were analyzed by monitoring mitochondrially-targeted red fluorescent protein. Adenovirus-driven overexpression of WT-Mfn1 elicited severe aggregation of mitochondria, preventing them from reaching peripheral near plasma membrane areas of the cell. Overexpression of DN-Mfn1 resulted in fragmented mitochondria with widespread cytosolic distribution. WT-Mfn1 overexpression impaired mitochondrial function as glucose- and oligomycin-induced mitochondrial hyperpolarization were markedly reduced. Viability of the INS-1E cells, however, was not affected. Mitochondrial motility was significantly reduced in WT-Mfn1 overexpressing cells. Conversely, fragmented mitochondria in DN-Mfn1 overexpressing cells showed more vigorous movement than mitochondria in control cells. Movement of these mitochondria was also less microtubule-dependent. These results suggest that Mfn1-induced hyperfusion leads to mitochondrial dysfunction and hypomotility, which may explain impaired metabolism-secretion coupling in insulin-releasing cells overexpressing Mfn1.

Mitochondrial transplantation: an overview of a promising therapeutic approach

  • Ji Soo Kim;Seonha Lee;Won-Kon Kim;Baek-Soo Han
    • BMB Reports
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    • 제56권9호
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    • pp.488-495
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    • 2023
  • Mitochondrial transplantation is a promising therapeutic approach for the treatment of mitochondrial diseases caused by mutations in mitochondrial DNA, as well as several metabolic and neurological disorders. Animal studies have shown that mitochondrial transplantation can improve cellular energy metabolism, restore mitochondrial function, and prevent cell death. However, challenges need to be addressed, such as the delivery of functional mitochondria to the correct cells in the body, and the long-term stability and function of the transplanted mitochondria. Researchers are exploring new methods for mitochondrial transplantation, including the use of nanoparticles or CRISPR gene editing. Mechanisms underlying the integration and function of transplanted mitochondria are complex and not fully understood, but research has revealed some key factors that play a role. While the safety and efficacy of mitochondrial transplantation have been investigated in animal models and human trials, more research is needed to optimize delivery methods and evaluate long-term safety and efficacy. Clinical trials using mitochondrial transplantation have shown mixed results, highlighting the need for further research in this area. In conclusion, although mitochondrial transplantation holds significant potential for the treatment of various diseases, more work is needed to overcome challenges and evaluate its safety and efficacy in human trials.

The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy

  • Tao, Li-Chan;Wang, Ting-ting;Zheng, Lu;Hua, Fei;Li, Jian-Jun
    • Biomolecules & Therapeutics
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    • 제30권5호
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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.

Alleviation of Senescence via ATM Inhibition in Accelerated Aging Models

  • Kuk, Myeong Uk;Kim, Jae Won;Lee, Young-Sam;Cho, Kyung A;Park, Joon Tae;Park, Sang Chul
    • Molecules and Cells
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    • 제42권3호
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    • pp.210-217
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    • 2019
  • The maintenance of mitochondrial function is closely linked to the control of senescence. In our previous study, we uncovered a novel mechanism in which senescence amelioration in normal aging cells is mediated by the recovered mitochondrial function upon Ataxia telangiectasia mutated (ATM) inhibition. However, it remains elusive whether this mechanism is also applicable to senescence amelioration in accelerated aging cells. In this study, we examined the role of ATM inhibition on mitochondrial function in Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) cells. We found that ATM inhibition induced mitochondrial functional recovery accompanied by metabolic reprogramming, which has been known to be a prerequisite for senescence alleviation in normal aging cells. Indeed, the induced mitochondrial metabolic reprogramming was coupled with senescence amelioration in accelerated aging cells. Furthermore, the therapeutic effect via ATM inhibition was observed in HGPS as evidenced by reduced progerin accumulation with concomitant decrease of abnormal nuclear morphology. Taken together, our data indicate that the mitochondrial functional recovery by ATM inhibition might represent a promising strategy to ameliorate the accelerated aging phenotypes and to treat age-related disease.

Hypermethylation-mediated silencing of NDRG4 promotes pancreatic ductal adenocarcinoma by regulating mitochondrial function

  • Shi, Hao-Hong;Liu, Hai-E;Luo, Xing-Jing
    • BMB Reports
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    • 제53권12호
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    • pp.658-663
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    • 2020
  • The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors. Functionally, NDRGs play an important role in the malignant progression of cancer cells. However, little is known about the potential implications of NDRG4 in pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to elucidate the expression pattern of NDRG4 in PDAC and evaluate its potential cellular biological effects. Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function. Data mining demonstrated that NDRG4 was significantly down-regulated in PDAC tissues and cells. PDAC patients with low NDRG4 expression showed poor prognosis. Epigenetic regulation by DNA methylation was closely associated with NDRG4 down-regulation. NDRG4 overexpression dramatically suppressed PDAC cell growth and metastasis. Further functional analysis demonstrated that up-regulated NDRG4 in SW1990 and Canpan1 cells resulted in attenuated mitochondrial function, including reduced ATP production, decreased mitochondrial membrane potential, and increased fragmented mitochondria. However, opposite results were obtained for HPNE cells with NDRG4 knockdown. These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients.

Mitochondrial Transplantation Ameliorates the Development and Progression of Osteoarthritis

  • A Ram Lee;Jin Seok Woo;Seon-Yeong Lee;Hyun Sik Na;Keun-Hyung Cho;Yeon Su Lee;Jeong Su Lee;Seon Ae Kim;Sung-Hwan Park;Seok Jung Kim;Mi-La Cho
    • IMMUNE NETWORK
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    • 제22권2호
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    • pp.14.1-14.17
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    • 2022
  • Osteoarthritis (OA) is a common degenerative joint disease characterized by breakdown of joint cartilage. Mitochondrial dysfunction of the chondrocyte is a risk factor for OA progression. We examined the therapeutic potential of mitochondrial transplantation for OA. Mitochondria were injected into the knee joint of monosodium iodoacetate-induced OA rats. Chondrocytes from OA rats or patients with OA were cultured to examine mitochondrial function in cellular pathophysiology. Pain, cartilage destruction, and bone loss were improved in mitochondrial transplanted-OA rats. The transcript levels of IL-1β, TNF-α, matrix metallopeptidase 13, and MCP-1 in cartilage were markedly decreased by mitochondrial transplantation. Mitochondrial function, as indicated by membrane potential and oxygen consumption rate, in chondrocytes from OA rats was improved by mitochondrial transplantation. Likewise, the mitochondrial function of chondrocytes from OA patients was improved by coculture with mitochondria. Furthermore, inflammatory cell death was significantly decreased by coculture with mitochondria. Mitochondrial transplantation ameliorated OA progression, which is caused by mitochondrial dysfunction. These results suggest the therapeutic potential of mitochondrial transplantation for OA.

Effects of cisplatin on mitochondrial function and autophagy-related proteins in skeletal muscle of rats

  • Seo, Dae Yun;Bae, Jun Hyun;Zhang, Didi;Song, Wook;Kwak, Hyo-Bum;Heo, Jun-Won;Jung, Su-Jeen;Yun, Hyeong Rok;Kim, Tae Nyun;Lee, Sang Ho;Kim, Amy Hyein;Jeong, Dae Hoon;Kim, Hyoung Kyu;Han, Jin
    • BMB Reports
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    • 제54권11호
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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.

An experimental approach to study the function of mitochondria in cardiomyopathy

  • Chung, Youn Wook;Kang, Seok-Min
    • BMB Reports
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    • 제48권10호
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    • pp.541-548
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    • 2015
  • Cardiomyopathy is an inherited or acquired disease of the myocardium, which can result in severe ventricular dysfunction. Mitochondrial dysfunction is involved in the pathological process of cardiomyopathy. Many dysfunctions in cardiac mitochondria are consequences of mutations in nuclear or mitochondrial DNA followed by alterations in transcriptional regulation, mitochondrial protein function, and mitochondrial dynamics and energetics, presenting with associated multisystem mitochondrial disorders. To ensure correct diagnosis and optimal management of mitochondrial dysfunction in cardiomyopathy caused by multiple pathogenesis, multidisciplinary approaches are required, and to integrate between clinical and basic sciences, ideal translational models are needed. In this review, we will focus on experimental models to provide insights into basic mitochondrial physiology and detailed underlying mechanisms of cardiomyopathy and current mitochondria-targeted therapies for cardiomyopathy.

Oocyte quality is closely linked to DRP1 derived-mitochondrial fission and mitophagy by the NAD+ biosynthesis in a postovulatory-aging model of pigs

  • Ji-Hyun Shin;Seul-Gi Yang;Hyo-Jin Park;Deog-Bon Koo
    • 한국동물생명공학회지
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    • 제39권2호
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    • pp.67-80
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    • 2024
  • Background: Post-ovulatory aging (POA) of oocytes is related to a decrease in the quality and quantity of oocytes caused by aging. Previous studies on the characteristics of POA have investigated injury to early embryonic developmental ability, but no information is available on its effects on mitochondrial fission and mitophagy-related responses. In this study, we aimed to elucidate the molecular mechanisms underlying mitochondrial fission and mitophagy in in vitro maturation (IVM) oocytes and a POA model based on RNA sequencing analysis. Methods: The POA model was obtained through an additional 24 h culture following the IVM of matured oocytes. NMN treatment was administered at a concentration of 25 μM during the oocyte culture process. We conducted MitoTracker staining and Western blot experiments to confirm changes in mitochondrial function between the IVM and POA groups. Additionally, comparative transcriptome analysis was performed to identify differentially expressed genes and associated changes in mitochondrial dynamics between porcine IVM and POA model oocytes. Results: In total, 32 common genes of apoptosis and 42 mitochondrial fission and function uniquely expressed genes were detected (≥ 1.5-fold change) in POA and porcine metaphase II oocytes, respectively. Functional analyses of mitochondrial fission, oxidative stress, mitophagy, autophagy, and cellular apoptosis were observed as the major changes in regulated biological processes for oocyte quality and maturation ability compared with the POA model. Additionally, we revealed that the activation of NAD+ by nicotinamide mononucleotide not only partly improved oocyte quality but also mitochondrial fission and mitophagy activation in the POA porcine model. Conclusions: In summary, our data indicate that mitochondrial fission and function play roles in controlling oxidative stress, mitophagy, and apoptosis during maturation in POA porcine oocytes. Additionally, we found that NAD+ biosynthesis is an important pathway that mediates the effects of DRP1-derived mitochondrial morphology, dynamic balance, and mitophagy in the POA model.

난소절제와 Genistein 투여가 간 미토콘드리아 기능에 미치는 영향 (Effect of Ovariectomy and Genistein on Hepatic Mitochondrial Function)

  • 이영민;정명호;이연숙;송지현
    • Journal of Nutrition and Health
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    • 제37권9호
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    • pp.786-793
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    • 2004
  • Women with menopause or rats with ovariectomy is associated with increased body weight, body fat and insulin resistance, which are components of metabolic syndrome. Increased prevalence of metabolic syndrome after menopause might be associated with mitochondrial dysfunction, since mitochondrial oxidative and phosphorylation activity is strongly correlated with insulin sensitivity. Although estradiol replacement prevents the metabolic syndrome, harmful effect of estradiol hampers the casual usage to prevent the metabolic syndrome. It has been reported that genistein has a mild estrogenic activity, decreases fat mass in mice and has an antidiabetic role in diabetic rats. Although insulin resistance is closely related to mitochondrial functions, there has not been yet any study in regard to the effect of dietary genistein on mitochondrial function in the insulin resistant female subjects induced by ovariectomy or similar situation. The present study investigated whether the supplementation of genistein in the high fat diet affected the mitochondrial function of high fat fed ovariectomized rats. Female Sprague Dawley rats (8 weeks old) were assigned to the following groups: sham-operated+ high fat diet (S, n=6); sham-operated + high fat diet with 0.1% genistein (S + G, n=7); ovariectomized + high fat diet (OVX, n=8); ovariectomized + high fat diet with 0.1% genistein (OVX+ G, n=8). Ovariectomy significantly increased body weight compared with S group. Genistein consumption in ovariectomized (OVX + G) rats decreased body weight gain compared with OVX rats. Liver weights were increased by ovariectomy. The hepatic mitochondrial protein density expressed as mg per g liver was lower in the OVX group than in the S group. However, OVX + G group showed the increased mitochondrial protein density similar to the level of S group. When mRNA levels of genes related to mitochondria such as peroxisome proliferator-activated receptor ${\gamma}$ coactivator 1 (PGC-1) and cytochrome c oxidase subunit III (COX III) were measured, there were decreases in the mRNA levels of PGC-1 and COX III in S + G, OVX and OVX + G group. The activity of cytochrome c oxidase was not different between groups. We could observe the decrease in succinate dehydrogenase (SDH) activity per g liver in OVX rats. Genistein supplement increased SDH activity. In conclusion, genistein supplementation to the OVX rats enhanced mitochondrial function by increasing mitochondrial protein density and SDH activity. The improvement in mitochondrial function by genistein can contribute to the improvement in metabolic syndrome.