Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.

• MeSH
• cílená molekulární terapie * MeSH
• lidé MeSH
• mitochondriální nemoci farmakoterapie   metabolismus   patologie   MeSH
• mitochondrie metabolismus   patologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• respirační komplex II metabolismus   MeSH
• transport elektronů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients. METHODS: We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients. RESULTS: ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue. CONCLUSIONS: Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.

• MeSH
• antigeny nádorové MeSH
• dospělí MeSH
• karboanhydrasa IX metabolismus   genetika   MeSH
• karcinom z renálních buněk * patologie   metabolismus   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondriální DNA genetika   metabolismus   MeSH
• mitochondrie * metabolismus   patologie   genetika   MeSH
• mutace MeSH
• nádorový supresorový protein VHL genetika   metabolismus   MeSH
• nádory ledvin * patologie   metabolismus   genetika   MeSH
• respirační komplex II * metabolismus   genetika   MeSH
• senioři MeSH
• sukcinátdehydrogenasa genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited.

• MeSH
• lidé MeSH
• mitochondrie enzymologie   metabolismus   MeSH
• sukcinátdehydrogenasa metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

With the arrival of the third millennium, in spite of unprecedented progress in molecular medicine, cancer remains as untamed as ever. The complexity of tumours, dictating the potential response of cancer cells to anti-cancer agents, has been recently highlighted in a landmark paper by Weinberg and Hanahan on hallmarks of cancer [1]. Together with the recently published papers on the complexity of tumours in patients and even within the same tumour (see below), the cure for this pathology seems to be an elusive goal. Indisputably, the strategy ought to be changed, searching for targets that are generally invariant across the landscape of neoplastic diseases. One such target appears to be the mitochondrial complex II (CII) of the electron transfer chain, a recent focus of research. We document and highlight this particularly intriguing target in this review paper and give examples of drugs that use CII as their molecular target. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.

• MeSH
• antitumorózní látky chemie   klasifikace   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• biologické modely MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• respirační komplex II antagonisté a inhibitory   metabolismus   MeSH
• transport elektronů účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Mitochondrial complex II or succinate dehydrogenase (SDH) is at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. It has been shown that Sdh5 (SDHAF2/SDH5 in mammals) is required for flavination of the subunit Sdh1 (SDHA in human cells) in yeast. Here we demonstrate that in human breast cancer cells, SDHAF2/SDH5 is dispensable for SDHA flavination. In contrast to yeast, CRISPR-Cas9 nickase-mediated SDHAF2 KO breast cancer cells feature flavinated SDHA and retain fully assembled and functional complex II, as well as normal mitochondrial respiration. Our data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism.

• MeSH
• flaviny MeSH
• genový knockdown MeSH
• lidé MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• mitochondrie genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• nádory prsu genetika   metabolismus   MeSH
• posttranslační úpravy proteinů * MeSH
• respirační komplex II genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Respiratory complex II (CII, succinate dehydrogenase, SDH) inhibition can induce cell death, but the mechanistic details need clarification. To elucidate the role of reactive oxygen species (ROS) formation upon the ubiquinone-binding (Qp) site blockade, we substituted CII subunit C (SDHC) residues lining the Qp site by site-directed mutagenesis. Cell lines carrying these mutations were characterized on the bases of CII activity and exposed to Qp site inhibitors MitoVES, thenoyltrifluoroacetone (TTFA) and Atpenin A5. We found that I56F and S68A SDHC variants, which support succinate-mediated respiration and maintain low intracellular succinate, were less efficiently inhibited by MitoVES than the wild-type (WT) variant. Importantly, associated ROS generation and cell death induction was also impaired, and cell death in the WT cells was malonate and catalase sensitive. In contrast, the S68A variant was much more susceptible to TTFA inhibition than the I56F variant or the WT CII, which was again reflected by enhanced ROS formation and increased malonate- and catalase-sensitive cell death induction. The R72C variant that accumulates intracellular succinate due to compromised CII activity was resistant to MitoVES and TTFA treatment and did not increase ROS, even though TTFA efficiently generated ROS at low succinate in mitochondria isolated from R72C cells. Similarly, the high-affinity Qp site inhibitor Atpenin A5 rapidly increased intracellular succinate in WT cells but did not induce ROS or cell death, unlike MitoVES and TTFA that upregulated succinate only moderately. These results demonstrate that cell death initiation upon CII inhibition depends on ROS and that the extent of cell death correlates with the potency of inhibition at the Qp site unless intracellular succinate is high. In addition, this validates the Qp site of CII as a target for cell death induction with relevance to cancer therapy.

• MeSH
• buněčná smrt fyziologie   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mitochondrie metabolismus   fyziologie   MeSH
• molekulární sekvence - údaje MeSH
• mutageneze cílená MeSH
• respirační komplex II chemie   genetika   metabolismus   fyziologie   MeSH
• sekvence aminokyselin MeSH
• ubichinon chemie   genetika   metabolismus   MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial α-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• hexokinasa metabolismus   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondriální membrány účinky léků   MeSH
• mitochondrie účinky léků   MeSH
• nádorové buněčné linie MeSH
• napětím ovládaný aniontový kanál 1 metabolismus   MeSH
• peptidy farmakologie   MeSH
• povrchově aktivní látky farmakologie   MeSH
• sekvence aminokyselin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The mitochondrial respiratory chain (MRC) complex III (CIII) associates with complexes I and IV (CI and CIV) into supercomplexes. We identified a novel homozygous missense mutation (c.665G>C; p.Gly222Ala) in UQCRC2 coding for structural subunit Core 2 in a patient with severe encephalomyopathy. The structural data suggest that the Gly222Ala exchange might result in an altered spatial arrangement in part of the UQCRC2 subunit, which could impact specific protein-protein interactions. Accordingly, we have found decreased levels of CIII and accumulation of CIII-specific subassemblies comprising MT-CYB, UQCRB, UQCRQ, UQCR10 and CYC1 subunits, but devoid of UQCRC1, UQCRC2, and UQCRFS1 in the patient's fibroblasts. The lack of UQCRC1 subunit-containing subassemblies could result from an impaired interaction with mutant UQCRC2Gly222Ala and subsequent degradation of both subunits by mitochondrial proteases. Indeed, we show an elevated amount of matrix CLPP protease, suggesting the activation of the mitochondrial protein quality control machinery in UQCRC2Gly222Ala fibroblasts. In line with growing evidence, we observed a rate-limiting character of CIII availability for the supercomplex formation, accompanied by a diminished amount of CI. Furthermore, we found impaired electron flux between CI and CIII in skeletal muscle and fibroblasts of the UQCRC2Gly222Ala patient. The ectopic expression of wild-type UQCRC2 in patient cells rescued maximal respiration rate, demonstrating the deleterious effect of the mutation on MRC. Our study expands the phenotypic spectrum of human disease caused by CIII Core protein deficiency, provides insight into the assembly pathway of human CIII, and supports the requirement of assembled CIII for a proper accumulation of CI.

• MeSH
• fibroblasty patologie   MeSH
• homozygot MeSH
• kosterní svaly patologie   MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mitochondriální encefalomyopatie genetika   MeSH
• mitochondriální proteiny genetika   MeSH
• mitochondrie genetika   MeSH
• respirační komplex III genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Introduction and Objectives: One of the characteristic changes of tumor formation is accumulation of genetic disorders in mitochondrial and nuclear genome. Mitochondrial disorders, from its side, are responsible for failure of metabolism, apoptosis, cell growth, formation of reactive oxygen species, etc. Overprpoduction of reactive oxygen species (ROS) significantly impacts the respiration chain enzymes and entirely the antioxidant system of mitochondria. Finally this may become a favorable condition for normal cells transformation. The purpose of the presented work was to study the mitochondrial defects and to establish their role in prostate cancer development. Results: Experimental results demonstrate significant increase of the activity of mitochondrial succinate dehydrogenaze (complex II) of the malignant epithelial cells of prostate, and slight changes in cytochrome oxydase (complex IV) activity. Also significant activation of the antioxidant system (glutathione-dependant system) of mitochondria in prostate malignant epithelial cells was revealed. Conclusion: The above mentioned mitochondrial changes (II and IV complexes of respiration chain, activity of the antioxidant system) partially demonstrate the alterations in mitochondrial energy metabolism, which from its side, may indicate to resistance of prostate cancer cells and correspondingly to intensification of proliferation processes.

• MeSH
• citrátový cyklus MeSH
• glutathion metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitochondriální DNA * genetika   metabolismus   genetika   izolace a purifikace   metabolismus   MeSH
• nádory prostaty * genetika   MeSH
• přenos energie MeSH
• reaktivní formy kyslíku * MeSH
• respirační komplex IV MeSH
• senioři MeSH
• sukcinátdehydrogenasa * diagnostické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH

Mitochondrial respiratory chain is organised into supramolecular structures that can be preserved in mild detergent solubilisates and resolved by native electrophoretic systems. Supercomplexes of respiratory complexes I, III and IV as well as multimeric forms of ATP synthase are well established. However, the involvement of complex II, linking respiratory chain with tricarboxylic acid cycle, in mitochondrial supercomplexes is questionable. Here we show that digitonin-solubilised complex II quantitatively forms high molecular weight structures (CIIhmw) that can be resolved by clear native electrophoresis. CIIhmw structures are enzymatically active and differ in electrophoretic mobility between tissues (500 - over 1000 kDa) and cultured cells (400-670 kDa). While their formation is unaffected by isolated defects in other respiratory chain complexes, they are destabilised in mtDNA-depleted, rho0 cells. Molecular interactions responsible for the assembly of CIIhmw are rather weak with the complexes being more stable in tissues than in cultured cells. While electrophoretic studies and immunoprecipitation experiments of CIIhmw do not indicate specific interactions with the respiratory chain complexes I, III or IV or enzymes of the tricarboxylic acid cycle, they point out to a specific interaction between CII and ATP synthase.

• MeSH
• buněčné linie MeSH
• elektronový transportní řetězec chemie   metabolismus   MeSH
• lidé MeSH
• metabolické sítě a dráhy MeSH
• mitochondrie genetika   metabolismus   MeSH
• molekulová hmotnost MeSH
• orgánová specificita MeSH
• oxidativní fosforylace MeSH
• respirační komplex II chemie   metabolismus   MeSH
• transport elektronů MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH