Mechanistic insight of mitochondrial dysfunctions in cardiovascular diseases with potential biomarkers

Islam Md. Nazmul,Mishra Vineet Kumar,Munalisa Rina,Parveen Farzana,Ali Saieeda Fabia,Akter Khadiza,Ahmed Tanvir,Ho Tsung-Jung,Huang Chih-Yang 대한독성 유전단백체 학회 2024 Molecular & cellular toxicology Vol.20 No.3

Background Acceleration of atherogenesis is an aftermath of cardiovascular diseases (CVDs), which arise with mitochondrial dysfunction (MD). Endothelium restraint inflammation, repair and fluidic exchange with nearby tissues. Endothelium-mediated mitochondrial damage can trigger the molecular mechanisms of vasodilation, pro-inflammation and process of pro-thrombotic accumulation in microvascular endothelial layer. The oxidation of lipid particles generates modified lipoproteins. Modification of mitochondrial function recently emerged a great concern towards the atherosclerosis initiation and progression, because the powerhouse of energy production mitochondria mutation can release mtDNA into cytoplasm and it can be act as sensor for viral DNA or foreign DNA. Another cause is mitochondrial imbalance can lead to product excess amount of reactive oxygen species (ROS) which can cause cellular metabolism and respiration system. Objectives In previous some studies showed that mitochondrial dysfunction plays a vital role in term of cardiac diseases. However, very few studies provide evidence of endothelium-mediated mitochondrial imbalance. This study investigated the potential involvement of mitochondrial impairment in cardiotoxicity using a series of mechanistic endpoints, including mitochondrial respiration and endothelial suppression of inflammation, mitochondrial DNA. Our study provides some molecular mechanisms regarding mitochondrial role in endothelium function. In each section, we are trying to introduce key concepts and then analysis previous studies revealed the importance of that molecular mechanism regarding mitochondrial dysfunction. Conclusions The ultimate goal of our review is to find out the novel drug discovery or new approaches of therapy. Our review will target different aspects of mitochondrial protein function and their effect of endothelial and cause of atherosclerosis diseases. To evaluate the healthy lifestyle and better condition of mitochondrial balance nowadays it is urgent to utilize the proper function for therapeutical effect for future direction. Background Acceleration of atherogenesis is an aftermath of cardiovascular diseases (CVDs), which arise with mitochondrial dysfunction (MD). Endothelium restraint inflammation, repair and fluidic exchange with nearby tissues. Endothelium-mediated mitochondrial damage can trigger the molecular mechanisms of vasodilation, pro-inflammation and process of pro-thrombotic accumulation in microvascular endothelial layer. The oxidation of lipid particles generates modified lipoproteins. Modification of mitochondrial function recently emerged a great concern towards the atherosclerosis initiation and progression, because the powerhouse of energy production mitochondria mutation can release mtDNA into cytoplasm and it can be act as sensor for viral DNA or foreign DNA. Another cause is mitochondrial imbalance can lead to product excess amount of reactive oxygen species (ROS) which can cause cellular metabolism and respiration system. Objectives In previous some studies showed that mitochondrial dysfunction plays a vital role in term of cardiac diseases. However, very few studies provide evidence of endothelium-mediated mitochondrial imbalance. This study investigated the potential involvement of mitochondrial impairment in cardiotoxicity using a series of mechanistic endpoints, including mitochondrial respiration and endothelial suppression of inflammation, mitochondrial DNA. Our study provides some molecular mechanisms regarding mitochondrial role in endothelium function. In each section, we are trying to introduce key concepts and then analysis previous studies revealed the importance of that molecular mechanism regarding mitochondrial dysfunction. Conclusions The ultimate goal of our review is to find out the novel drug discovery or new approaches of therapy. Our review will target different aspects of mitochondrial protein function and their effect of endothelial and cause of atherosclerosis diseases. To evaluate the healthy lifestyle and better condition of mitochondrial balance nowadays it is urgent to utilize the proper function for therapeutical effect for future direction.

Mitochondrial Transplantation Ameliorates the Development and Progression of Osteoarthritis

이아람,우진석,이선영,나현식,조권형,이연수,이정수,김선애,박승환,김석중,조미라 대한면역학회 2022 Immune Network Vol.22 No.2

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.

ER Stress Is Implicated in Mitochondrial Dysfunction-Induced Apoptosis of Pancreatic Beta Cells

June Woo Lee,Won Ho Kim,여지영,정명호 한국분자세포생물학회 2010 Molecules and cells Vol.30 No.6

Mitochondrial dysfunction induces apoptosis of pancreatic β-cells and leads to type 2 diabetes, but the mechanism involved in this process remains unclear. Chronic endoplasmic reticulum (ER) stress plays a role in the apoptosis of pancreatic β-cells; therefore, in current study, we investigated the implication of ER stress in mitochondrial dysfunction-induced β-cells apoptosis. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, which are mouse pancreatic β-cells. Impaired mitochondria dysfunction increased ER stress proteins such as p-eIF2α, GRP78 and GRP 94, as well as ER stress-associated apoptotic factor,CHOP, and activated JNK. AMP-activated protein kinase (AMPK) was also activated under mitochondria dysfunction by metabolic stress. However, the inhibition of AMPK by treatment with compound C, inhibitor of AMPK, and overexpression of mutant dominant negative AMPK (AMPKK45R)blocked the induction of ER stress, which was consist-ent with the decreased β-cell apoptosis and increase of insulin content. Furthermore, mitochondrial dysfunction increased the expression of the inducible nitric oxide synthase (iNOS) gene and the production of nitric oxide (NO),but NO production was prevented by compound C and mutant dominant negative AMPK (AMPK-K45R). Moreover,treatment with 1400W, which is an inhibitor of iNOS, prevented ER stress and apoptosis induced by mitochondrial dysfunction. Treatment of MIN6N8 cells with lipid mixture,physiological conditions of impaired mitochondria function,activated AMPK, increased NO production and induced ER stress. Collectively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production, resulting in pancreatic β-cells apoptosis.

ER Stress Is Implicated in Mitochondrial Dysfunction-Induced Apoptosis of Pancreatic Beta Cells

Lee, June-Woo,Kim, Won-Ho,Yeo, Ji-Young,Jung, Myeong-Ho Korean Society for Molecular and Cellular Biology 2010 Molecules and cells Vol.30 No.6

Mitochondrial dysfunction induces apoptosis of pancreatic ${\beta}$-cells and leads to type 2 diabetes, but the mechanism involved in this process remains unclear. Chronic endoplasmic reticulum (ER) stress plays a role in the apoptosis of pancreatic ${\beta}$-cells; therefore, in current study, we investigated the implication of ER stress in mitochondrial dysfunction-induced ${\beta}$-cells apoptosis. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, which are mouse pancreatic ${\beta}$-cells. Impaired mitochondria dysfunction increased ER stress proteins such as p-eIF2${\alpha}$, GRP78 and GRP 94, as well as ER stress-associated apoptotic factor, CHOP, and activated JNK. AMP-activated protein kinase (AMPK) was also activated under mitochondria dysfunction by metabolic stress. However, the inhibition of AMPK by treatment with compound C, inhibitor of AMPK, and overexpression of mutant dominant negative AMPK (AMPK-K45R) blocked the induction of ER stress, which was consistent with the decreased ${\beta}$-cell apoptosis and increase of insulin content. Furthermore, mitochondrial dysfunction increased the expression of the inducible nitric oxide synthase (iNOS) gene and the production of nitric oxide (NO), but NO production was prevented by compound C and mutant dominant negative AMPK (AMPK-K45R). Moreover, treatment with 1400W, which is an inhibitor of iNOS, prevented ER stress and apoptosis induced by mitochondrial dysfunction. Treatment of MIN6N8 cells with lipid mixture, physiological conditions of impaired mitochondria function, activated AMPK, increased NO production and induced ER stress. Collectively, these data demonstrate that mitochondrial dysfunction activates AMPK, which induces ER stress via NO production, resulting in pancreatic ${\beta}$-cells apoptosis.

Mitochondrial dysfunction suppresses p53 expression via calcium-mediated nuclear factor-kB signaling in HCT116 human colorectal carcinoma cells

( Young-kyoung Lee ),( Eui-yeun Yi ),( Shi-young Park ),( Won-jun Jang ),( Yu-seon Han ),( Myeong-eun Jegal ),( Yung-jin Kim ) 생화학분자생물학회 2018 BMB Reports Vol.51 No.6

Mitochondrial DNA (mtDNA) mutations are often observed in various cancer types. Although the correlation between mitochondrial dysfunction and cancer malignancy has been demonstrated by several studies, further research is required to elucidate the molecular mechanisms underlying accelerated tumor development and progression due to mitochondrial mutations. We generated an mtDNA-depleted cell line, ρ⁰, via long-term ethidium bromide treatment to define the molecular mechanisms of tumor malignancy induced by mitochondrial dysfunction. Mitochondrial dysfunction in ρ⁰ cells reduced drug-induced cell death and decreased the expression of pro-apoptotic proteins including p53. The p53 expression was reduced by activation of nuclear factor-κB that depended on elevated levels of free calcium in HCT116/ρ⁰ cells. Overall, these data provide a novel mechanism for tumor development and drug resistance due to mitochondrial dysfunction. [BMB Reports 2018; 51(6): 296-301]

Ginsenoside Rg3 Restores Hepatitis C Virus-Induced Aberrant Mitochondrial Dynamics and Inhibits Virus Propagation

( Jae Young Jang ),( Seong-jun Kim ),( Eun-jung Kim ),( Eun Kyung Cho ),( Dae-gyun Ahn ),( Chonsaeng Kim ),( Han Seul Park ),( Soung Won Jeong ),( Sae Hwan Lee ),( Sang Gyune Kim ),( Young Seok Kim ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their treatment of patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine and other conditions, which may be linked to mitochondrial dysfunction. Methods: Here we show that clinically prescribed DAAs, including Sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV- and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of the mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Results: Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited the notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21 required for increasing the cyclin-dependent kinase 1 (CDK1) activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1 (Drp1). The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment (figure). Conclusions: G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced Drp1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection.

Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

신소연,김재영,이주연,김준,오창명 대한비만학회 2023 Journal of obesity & metabolic syndrome Vol.32 No.4

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is characterized by hepatic steatosis and metabolic dysfunction and is often associated with obesity and insulin resistance. Recent research indicates a rapid escalation in MASLD cases, with projections suggesting a doubling in the United States by 2030. This review focuses on the central role of mitochondria in the pathogenesis of MASLD and explores potential therapeutic interventions. Mitochondria are dynamic organelles that orchestrate hepatic energy production and metabolism and are critically involved in MASLD. Dysfunctional mitochondria contribute to lipid accumulation, inflammation, and liver fibrosis. Genetic associations further underscore the relationship between mitochondrial dynamics and MASLD susceptibility. Although U.S. Food and Drug Administration-approved treatments for MASLD remain elusive, ongoing clinical trials have highlighted promising strategies that target mitochondrial dysfunction, including vitamin E, metformin, and glucagon-like peptide-1 receptor agonists. In preclinical studies, novel therapeutics, including nicotinamide adenine dinucleotide+ precursors, urolithin A, spermidine, and mitoquinone, have shown beneficial effects, such as improving mitochondrial quality control, reducing oxidative stress, and ameliorating hepatic steatosis and inflammation. In conclusion, mitochondrial dysfunction is central to MASLD pathogenesis. The innovative mitochondria-targeted approaches discussed in this review offer a promising avenue for reducing the burden of MASLD and improving global quality of life.

Adenine Nucleotide Translocator as a Regulator of Mitochondrial Function: Implication in the Pathogenesis of Metabolic Syndrome

김은희,고은희,박중열,이기업 대한당뇨병학회 2010 Diabetes and Metabolism Journal Vol.34 No.3

Mitochondria play key roles in energy production and intracellular reactive oxygen species (ROS) generation. Lines of evidence have shown that mitochondrial dysfunction contributes to the development of metabolic syndrome. The causes of mitochondrial dysfunction are complex, but overnutrition and sedentary living are among the best known causes of mitochondrial dysfunction. ATP synthesized in the mitochondria is exchanged for cytosolic ADP by adenine nucleotide translocator (ANT) to provide a continuous supply of ADP to mitochondria. We recently found that ANT function is essential for peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α)’s action on endothelial cells. PGC-1α is a transcriptional coactivator of nuclear receptors,playing an important role in fatty acid oxidation and mitochondrial biogenesis. Recent studies have shown that PGC-1αdecreases intracellular ROS generation by increasing the expression of antioxidant genes. In our study, PGC-1α reduced cell apoptosis and ROS generation in endothelial cells by increasing ATP/ADP translocase activity of ANT and ANT1 expression. Here we review the role of ANT in maintaining proper mitochondrial function, and possible role of ANT dysfunction in the pathogenesis of metabolic syndrome.

트레드밀 지구성 운동이 알츠하이머 형질전환 생쥐 뇌의 Mitochondrial Dynamic과 신경세포생존에 미치는 영향

구정훈 ( Jung Hoon Koo ),조인호 ( In Ho Cho ) 한국운동생리학회 2016 운동과학 Vol.25 No.1

PURPOSE: The aim of this study was to investigate effects of treadmill exercise on mitochondrial beta-amyloid protein, mitochondrial dynamic function and neuronal cell survival of brain cortex mitochondria in transgenic mice model with Alzheimer’s disease METHODS: Fifteen transgenic mice with Alzheimer’s disease were divided into three groups: (1) Non transgenic control (NTC, n=5), (2) transgenic control (TC, n=5) and (3) ransgenic-exercise (TE, n=5). TE mice group was subjected to treadmill exercise on a treadmill for 12 weeks (15 m/min, 60 min/day, 5 day/week), And brain cortex mitochondria were evaluated to determine any changes in the A-42, neuronal cell survival-related proteins, Sirt-3, SOD-2, and mitochondrial dynamic-related proteins. RESULTS: Treadmill exercise decreased A-42 and mitochondiral fission proteins (Drp 1, Fis 1) in the brain cortex mitochondria while it increased Sirt-3, SOD-2 and mitochondrial fusion proteins (Mfn 1, Mfn 2, Opa 1) and neuronal cell survival factors (Bcl-2/Bax ratio, mito-cytochrome c/cyto-cytochrome c ratio). Moreover, treadmill exercise improved spatial learning and cognitive function in TE group. CONCLUSIONS: Treadmill exercise protects against Aβ-induced imbalance of mitochondrial dynamic function and neuronal cell death through decreasing Aβprotein and mitochondria fission and activating mitochondrial fusion, indicating that treadmill exercise may play a role in a preventive strategy for AD-related mitochondrial dysfunction.

P53 knockout mice are protected from cocaine-induced kindling behaviors via inhibiting mitochondrial oxidative burdens, mitochondrial dysfunction, and proapoptotic changes

Mai, Huynh Nhu,Sharma, Naveen,Jeong, Ji Hoon,Shin, Eun-Joo,Pham, Duc Toan,Trinh, Quynh Dieu,Lee, Yu Jeung,Jang, Choon-Gon,Nah, Seung-Yeol,Bing, Guoying,Kim, Hyoung-Chun Elsevier 2019 Neurochemistry International Vol.124 No.-

<P><B>Abstract</B></P> <P>Previously we demonstrated that p53 mediates dopaminergic neurotoxicity via inducing mitochondrial burdens and proapoptotsis. However, little is known about the role of p53 in the excitotoxicity induced by psychostimulant, such as cocaine. Cocaine-induced kindling (convulsive) behaviors significantly increased p53 expression in the brain. Cocaine-induced p53 expression was more pronounced in hippocampus than in striatum or prefrontal cortex. Genetic depletion of p53 significantly attenuated cocaine-induced convulsive behaviors, followed by c-Fos immunoreactivity, and oxidative burdens in the hippocampus of mice. The antioxidant potentials mediated by genetic depletion of p53 were more pronounced in the mitochondrial-than cytosolic-fraction. Depletion of p53 significantly attenuated the changes in mitochondrial transmembrane potential, intramitochondrial Ca<SUP>2+</SUP> level, and mitochondrial oxidative burdens induced by cocaine. Consistently, depletion of p53 significantly inhibited mitochondrial p53 translocation, and cleaved-PKCδ induced by cocaine. In addition, depletion of p53 protected from cytosolic cytochrome c release, and pro-apoptotic changes induced by cocaine. Importantly, the protective/anticonvulsant potentials by genetic depletion of p53 were comparable to those by pifithrin-μ (PFT), a p53 inhibitor. Our results suggest that depletion of p53 offers anticonvulsive and neuroprotective potentials mainly via attenuating mitochondrial oxidative burdens, mitochondrial dysfunction, and pro-apoptotic signalings against cocaine-induced convulsive neurotoxicity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> P53 inhibition protects against cocaine-induced kindling (convulsive) behaviors. </LI> <LI> Cocaine-induced p53 expression is most pronounced in hippocampus. </LI> <LI> Cocaine-induced oxidative stress is more evident in mitochondria than in cytosol. </LI> <LI> P53 depletion attenuates cocaine-induced mitochondrial dysfunction. </LI> <LI> P53 depletion attenuates cocaine-induced pro-apoptotic phenomena. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>