Mitochondria are vital organelles with their own DNA (mtDNA). mtDNA is circular and composed of heavy and light chains that are structurally more accessible than nuclear DNA (nDNA). While nDNA is typically diploid, the number of mtDNA copies per cell is higher and varies considerably during development and between tissues. Compared with nDNA, mtDNA is more prone to damage that is positively linked to many diseases, including cancer. Similar to nDNA, mtDNA undergoes repair processes, although these mechanisms are less well understood. In this review, we discuss the various forms of mtDNA damage and repair and their association with cancer initiation and progression. We also propose horizontal mitochondrial transfer as a novel mechanism for replacing damaged mtDNA.

• Klíčová slova
• DNA stability, base excision repair, cancer, horizontal mitochondrial transfer, mitochondrial DNA, mitochondrial DNA damage repair, nuclear DNA,
• MeSH
• lidé MeSH
• mitochondriální DNA * genetika   MeSH
• mitochondrie * genetika   metabolismus   MeSH
• nádory * genetika   patologie   MeSH
• oprava DNA * MeSH
• poškození DNA * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• mitochondriální DNA * MeSH

The concentration-dependence of tert-butyl hydroperoxide (BHP) inhibitory effect on oxygen consumption in isolated rat liver mitochondria was measured in the presence of various respiratory substrates. Strong inhibitory effect at low concentrations of BHP (15-30 microM) was found for oxoglutarate and palmitoyl carnitine oxidation. Pyruvate and glutamate oxidation was inhibited at higher concentrations of BHP (100-200 microM). Succinate oxidation was not affected even at 3.3 mM BHP. Determination of mitochondrial membrane potential has shown that in the presence of NADH-dependent substrates the membrane potential was dissipated by BHP but was completely restored after addition of succinate. Our data thus indicate that beside peroxidative damage of complex I also various mitochondrial NADH-dependent dehydrogenases are inhibited, but to a different extent and with different kinetics. Our data also show that succinate could be an important nutritional substrate protecting hepatocytes during peroxidative damage.

• MeSH
• buněčné dýchání MeSH
• jaterní mitochondrie metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina glutamová metabolismus   MeSH
• kyselina jantarová metabolismus   MeSH
• kyselina pyrohroznová metabolismus   MeSH
• kyseliny ketoglutarové metabolismus   MeSH
• membránový potenciál mitochondrií MeSH
• oxidační stres * MeSH
• palmitoyl karnitin metabolismus   MeSH
• potkani Wistar MeSH
• spotřeba kyslíku MeSH
• terc-butylhydroperoxid farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina glutamová MeSH
• kyselina jantarová MeSH
• kyselina pyrohroznová MeSH
• kyseliny ketoglutarové MeSH
• palmitoyl karnitin MeSH
• terc-butylhydroperoxid MeSH

Cadmium crosses the blood-brain barrier inducing damage to neurons. Cell impairment is predominantly linked to oxidative stress and glutathione (GSH) depletion. On the other hand, several reports have described an increase of GSH levels in neuronal cells after CdCl2 exposure. Therefore, the aim of the present report was to investigate the relation between changes in GSH levels and mitochondrial damage in neuronal cells after CdCl2 treatment. To characterize neuronal impairment after CdCl2 treatment (0-200 μM) for 1-48 h, we used the SH-SY5Y cell line. We analyzed GSH metabolism and determined mitochondrial activity using high-resolution respirometry. CdCl2 treatment induced both the decreases and increases of GSH levels in SH-SY5Y cells. GSH concentration was significantly increased in cells incubated with up to 50 μM CdCl2 but only 100 μM CdCl2 induced GSH depletion linked to increased ROS production. The overexpression of proteins involved in GSH synthesis increased in response to 50 and 100 μM CdCl2 after 6 h. Finally, strong mitochondrial impairment was detected even in 50 μM CdCl2 treated cells after 24 h. We conclude that a significant decrease in mitochondrial activity can be observed in 50 μM CdCl2 even without the occurrence of GSH depletion in SH-SY5Y cells.

• Klíčová slova
• Cadmium toxicity, Glutathione depletion, Mitochondrial damage, Neuronal cells, Oxidative stress,
• MeSH
• chlorid kademnatý * toxicita   MeSH
• glutathion * metabolismus   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• neurony * účinky léků   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chlorid kademnatý * MeSH
• glutathion * MeSH
• reaktivní formy kyslíku MeSH

We have investigated the cytotoxicity and specific effects of selenite in human bladder cancer cell line RT-112 and its clonogenic variant RT-112 HB. Selenite inhibited cell growth and proliferation in both cell lines. Treated cells developed extensive vacuolization which was dose independent but occurring in differing time frames. Ultrastructure analysis revealed that the observed vacuoles are damaged mitochondria and potentially other subcellular compartments. Selenite-specific effects on mitochondria were further confirmed by mitochondrial membrane potential analysis, changes in ATP production and generation of superoxide. Simultaneously, selenite induced DNA damage in treated cells with activation of p53, PARP-1 and JNK and suppressed autophagy. Cells ultimately died via a combination of apoptosis, necrosis and a distinct type of cell death featuring "vacuolar shrinkage", loss of adherence and absence of secondary necrosis as well as other classical markers of either apoptosis or autophagy. The significant presence of so called necroptosis was also not confirmed as the specific inhibitor necrostatin-1 could not prevent cell death. These results thus confirm the toxicity of selenite in bladder cancer cells while pointing at potentially new mechanism of action of this compound in this model.

• Klíčová slova
• Bladder cancer, DNA damage, Mitochondria, Necroptosis, Necrosis, Selenite,
• MeSH
• apoptóza účinky léků   MeSH
• kyselina seleničitá toxicita   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie účinky léků   fyziologie   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory močového měchýře metabolismus   patologie   MeSH
• nekróza chemicky indukované   MeSH
• poškození DNA * MeSH
• superoxidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina seleničitá MeSH
• nádorový supresorový protein p53 MeSH
• superoxidy MeSH

Huntington's disease (HD) is a progressive neurodegenerative disorder primarily affecting the basal ganglia and is caused by expanded CAG repeats in the huntingtin gene. Except for CAG sizing, mitochondrial and nuclear DNA (mtDNA and nDNA) parameters have not yet proven to be representative biomarkers for disease and future therapy. Here, we identified a general suppression of genes associated with aerobic metabolism in peripheral blood mononuclear cells (PBMCs) from HD patients compared to controls. In HD, the complex II subunit SDHB was lowered although not sufficiently to affect complex II activity. Nevertheless, we found decreased level of factors associated with mitochondrial biogenesis and an associated dampening of the mitochondrial DNA damage frequency in HD, implying an early defect in mitochondrial activity. In contrast to mtDNA, nDNA from HD patients was four-fold more modified than controls and demonstrated that nDNA integrity is severely reduced in HD. Interestingly, the level of nDNA damage correlated inversely with the total functional capacity (TFC) score; an established functional score of HD. Our data show that PBMCs are a promising source to monitor HD progression and highlights nDNA damage and diverging mitochondrial and nuclear genome responses representing early cellular impairments in HD.

• MeSH
• dospělí MeSH
• Huntingtonova nemoc genetika   patologie   MeSH
• leukocyty mononukleární metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondriální DNA analýza   genetika   MeSH
• mitochondrie metabolismus   patologie   MeSH
• mladý dospělý MeSH
• nestabilita genomu * MeSH
• poškození DNA * MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mitochondriální DNA MeSH

T-2 toxin, a major compound of trichothecenes, induces cell apoptosis and growth hormone (GH) deficiency and causes considerable growth retardation in animals and human cells. However, the mechanism underlying its growth suppression still remains unclear. Recent studies have suggested that ROS induced cell apoptosis and animal feed intake reduction, but there are limited reports on the role of RNS in T-2 toxin-mediated mitochondrial damage, cell apoptosis and growth retardation. Herein, T-2 toxin-induced GH3 cell damage and apoptosis were tested by MTT assay, LDH leakage and flow cytometry, respectively. Intracellular NO and antioxidant enzyme activity, ΔΨm, morphometric changes of mitochondria, the caspase pathway, and inflammatory factors were investigated. Free radical scavengers NAC, SOD and NO scavenger haemoglobin were used to explore the role of oxidative stress and the relationship between NO production and caspase pathway. The results clearly revealed that T-2 toxin caused significant increases in NO generation, cell apoptosis, GH deficiency, increased iNOS activity, upregulation of inflammatory factors and caspase pathway, decreases in ΔΨm and morphosis damage. These data suggest that mitochondria are a primary target of T-2 toxin-induced NO, and NO is a key mediator of T-2 toxin-induced cell apoptosis and GH deficiency via the mitochondria-dependent pathway in cells.

• Klíčová slova
• Caspase pathway, Cell apoptosis, Growth hormone deficiency, Mitochondrial damage, NO, T-2 toxin,
• MeSH
• adenohypofýza cytologie   MeSH
• apoptóza účinky léků   MeSH
• kaspasy metabolismus   MeSH
• krysa rodu Rattus MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• růstový hormon nedostatek   MeSH
• signální transdukce účinky léků   MeSH
• somatotropní buňky účinky léků   metabolismus   patologie   MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• T-2 toxin toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kaspasy MeSH
• Nos2 protein, rat MeSH Prohlížeč
• oxid dusnatý MeSH
• růstový hormon MeSH
• synthasa oxidu dusnatého, typ II MeSH
• T-2 toxin MeSH

Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (>48h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity.

• Klíčová slova
• Doxorubicin, Ethidium Bromide, Mitochondrial DNA stress, Mitochondrial transcription factor A, Nucleoid clusters,
• MeSH
• buňky Hep G2 MeSH
• DNA vazebné proteiny metabolismus   MeSH
• doxorubicin MeSH
• dynaminy MeSH
• ethidium MeSH
• GTP-fosfohydrolasy metabolismus   MeSH
• jaterní mitochondrie metabolismus   MeSH
• lidé MeSH
• mitochondriální DNA metabolismus   MeSH
• mitochondriální importní komplex MeSH
• mitochondriální proteiny metabolismus   MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• poškození DNA MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• transportní proteiny mitochondriální membrány metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• DNM1L protein, human MeSH Prohlížeč
• doxorubicin MeSH
• dynaminy MeSH
• ethidium MeSH
• GTP-fosfohydrolasy MeSH
• MAP1LC3B protein, human MeSH Prohlížeč
• mitochondriální DNA MeSH
• mitochondriální importní komplex MeSH
• mitochondriální proteiny MeSH
• NABP2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• proteiny asociované s mikrotubuly MeSH
• TFAM protein, human MeSH Prohlížeč
• TIMM23 protein, human MeSH Prohlížeč
• transkripční faktory MeSH
• transportní proteiny mitochondriální membrány MeSH

Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy.

• Klíčová slova
• Autophagy, Cancer predisposition syndromes, DNA damage and repair, Mitochondrial dysfunction, Mitophagy, Oxidative stress, ROS,
• MeSH
• autofagie MeSH
• lidé MeSH
• mitochondrie fyziologie   MeSH
• nádory etiologie   MeSH
• poškození DNA * MeSH
• syndrom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed Padina pavonica (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer's disease (AD) and Parkinson's disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome c from the mitochondria. Using cardiolipin-enriched synthetic lipid membranes, we also show that dye leakage from fluorophore-loaded vesicles and formation of channel-like pores in planar bilayer membranes are largely prevented by incubating the oligomeric aggregates with PPE. Lastly, we demonstrate that PPE curtails the ability of Aβ42 and α-syn monomers to self-assemble into larger β-aggregate structures, as well as potently disrupts their respective amyloid fibrils. In conclusion, the mito-protective and anti-aggregator biological activities of Padina pavonica extract may be of therapeutic value in neurodegenerative proteinopathies, such as AD and PD.

• Klíčová slova
• Alzheimer’s disease, Padina pavonica seaweed extract, Parkinson’s disease, amyloidogenic proteins, membrane permeabilization, mitochondria,
• MeSH
• alfa-synuklein metabolismus   toxicita   MeSH
• amyloidní beta-protein metabolismus   toxicita   MeSH
• lidé MeSH
• lipidové dvojvrstvy chemie   MeSH
• mitochondriální membrány účinky léků   patologie   MeSH
• mořské řasy chemie   MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• peptidové fragmenty metabolismus   toxicita   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• Phaeophyceae chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-synuklein MeSH
• amyloid beta-protein (1-42) MeSH Prohlížeč
• amyloidní beta-protein MeSH
• lipidové dvojvrstvy MeSH
• neuroprotektivní látky MeSH
• peptidové fragmenty MeSH

Mitochondrial dysfunction and accumulation of oxidative damage have been implicated to be the major factors of aging. However, data on age-related changes in activities of mitochondrial electron transport chain (ETC) complexes remain controversial and molecular mechanisms responsible for ETC dysfunction are still largely unknown. In this study, we examined the effect of aging on activities of ETC complexes and oxidative damage to proteins and lipids in cardiac mitochondria from adult (6-month-old), old (15-month-old) and senescent (26-month-old) rats. ETC complexes I-IV displayed different extent of inhibition with age. The most significant decline occurred in complex IV activity, whereas complex II activity was unchanged in old rats and was only slightly reduced in senescent rats. Compared to adult, old and senescent rat hearts had significantly higher levels of malondialdehyde, 4-hydroxynonenal (HNE) and dityrosine, while thiol group content was reduced. Despite marked increase in HNE content with age (25 and 76 % for 15- and 26-month-old rats, respectively) Western blot analysis revealed only few HNE-protein adducts. The present study suggests that non-uniform decline in activities of ETC complexes is due, at least in part, to mitochondrial oxidative damage; however, lipid peroxidation products appear to have a limited impact on enzyme functions.

• MeSH
• aldehydy metabolismus   MeSH
• elektronový transportní řetězec metabolismus   MeSH
• krysa rodu Rattus MeSH
• malondialdehyd metabolismus   MeSH
• myokard metabolismus   MeSH
• oxidační stres * MeSH
• peroxidace lipidů MeSH
• potkani Wistar MeSH
• srdeční mitochondrie chemie   metabolismus   MeSH
• stárnutí metabolismus   MeSH
• sulfhydrylové sloučeniny metabolismus   MeSH
• transport elektronů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-hydroxy-2-nonenal MeSH Prohlížeč
• aldehydy MeSH
• elektronový transportní řetězec MeSH
• malondialdehyd MeSH
• sulfhydrylové sloučeniny MeSH