Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial.

• Klíčová slova
• anti-cancer strategy, drug delivery, mitocans, mitochondrial targeting,
• MeSH
• chemorezistence účinky léků   MeSH
• cílená molekulární terapie MeSH
• citrátový cyklus účinky léků   MeSH
• elektronový transportní řetězec účinky léků   metabolismus   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádory farmakoterapie   metabolismus   MeSH
• oxidace-redukce účinky léků   MeSH
• progrese nemoci MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• elektronový transportní řetězec MeSH
• protinádorové látky MeSH

Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. Here, we provide evidence that an alternative mitochondrial complex II (CII) assembly, designated as CIIlow, serves as a checkpoint for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings suggest that CIIlow is a core complex inside mitochondria that provides homeostatic control of cellular metabolism depending on the availability of energy.

• MeSH
• biosyntetické dráhy fyziologie   MeSH
• energetický metabolismus fyziologie   MeSH
• fyziologický stres * MeSH
• genový knockout MeSH
• HEK293 buňky MeSH
• kontrolní body fáze S buněčného cyklu fyziologie   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• mutace MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• paragangliom genetika   patologie   MeSH
• respirační komplex II genetika   metabolismus   MeSH
• sukcinátdehydrogenasa genetika   metabolismus   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• malá interferující RNA MeSH
• respirační komplex II MeSH
• respiratory complex II MeSH Prohlížeč
• SDHA protein, human MeSH Prohlížeč
• SDHB protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH

The importance of iron in the growth and progression of tumors has been widely documented. In this report, we show that tumor-initiating cells (TICs), represented by spheres derived from the MCF7 cell line, exhibit higher intracellular labile iron pool, mitochondrial iron accumulation and are more susceptible to iron chelation. TICs also show activation of the IRP/IRE system, leading to higher iron uptake and decrease in iron storage, suggesting that level of properly assembled cytosolic iron-sulfur clusters (FeS) is reduced. This finding is confirmed by lower enzymatic activity of aconitase and FeS cluster biogenesis enzymes, as well as lower levels of reduced glutathione, implying reduced FeS clusters synthesis/utilization in TICs. Importantly, we have identified specific gene signature related to iron metabolism consisting of genes regulating iron uptake, mitochondrial FeS cluster biogenesis and hypoxic response (ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 and TFRC). Principal component analysis based on this signature is able to distinguish TICs from cancer cells in vitro and also Leukemia-initiating cells (LICs) from non-LICs in the mouse model of acute promyelocytic leukemia (APL). Majority of the described changes were also recapitulated in an alternative model represented by MCF7 cells resistant to tamoxifen (TAMR) that exhibit features of TICs. Our findings point to the critical importance of redox balance and iron metabolism-related genes and proteins in the context of cancer and TICs that could be potentially used for cancer diagnostics or therapy.

• Klíčová slova
• FeS cluster, breast cancer, iron metabolism, stem cells, tumor-initiating cells,
• MeSH
• akutní promyelocytární leukemie enzymologie   genetika   MeSH
• analýza hlavních komponent MeSH
• biologický transport MeSH
• buněčné sféroidy MeSH
• chelátory železa farmakologie   MeSH
• chemorezistence MeSH
• fenotyp MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mitochondrie enzymologie   MeSH
• myši transgenní MeSH
• nádorové kmenové buňky účinky léků   enzymologie   patologie   MeSH
• nádory prostaty farmakoterapie   enzymologie   genetika   patologie   MeSH
• nádory prsu farmakoterapie   enzymologie   genetika   patologie   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese enzymů MeSH
• regulace genové exprese u nádorů MeSH
• stanovení celkové genové exprese MeSH
• tamoxifen farmakologie   MeSH
• transkriptom * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chelátory železa MeSH
• protinádorové látky MeSH
• tamoxifen MeSH
• železo 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.

• Klíčová slova
• SDH assembly factor, SDHA, SDHAF2, assembly factor, cancer biology, cancer cells, cell biology, complex II assembly, flavin adenine dinucleotide, flavination, flavinylation, mammal, mitochondria, mitochondrial complex II, mitochondrial respiratory chain complex, succinate dehydrogenase,
• 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
• Názvy látek
• flaviny MeSH
• mitochondriální proteiny MeSH
• nádorové proteiny MeSH
• respirační komplex II MeSH
• SDHA protein, human MeSH Prohlížeč
• SDHAF2 protein, human MeSH Prohlížeč