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
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• sukcinátdehydrogenasa MeSH

AIMS: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. RESULTS: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. INNOVATION: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.

• Klíčová slova
• HER2, breast cancer, mitochondria, mitochondrially targeted tamoxifen, respirasome,
• MeSH
• biologické markery MeSH
• buněčná smrt účinky léků   MeSH
• buněčné dýchání účinky léků   MeSH
• cílená molekulární terapie MeSH
• elektronový transportní řetězec antagonisté a inhibitory   chemie   metabolismus   MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• receptor erbB-2 antagonisté a inhibitory   metabolismus   MeSH
• respirační komplex I antagonisté a inhibitory   chemie   metabolismus   MeSH
• tamoxifen farmakologie   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• elektronový transportní řetězec MeSH
• protinádorové látky MeSH
• reaktivní formy kyslíku MeSH
• receptor erbB-2 MeSH
• respirační komplex I MeSH
• tamoxifen MeSH

Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM.

• MeSH
• antigen CD24 metabolismus   MeSH
• buněčná adheze účinky léků   MeSH
• buněčné sféroidy účinky léků   patologie   MeSH
• fenotyp MeSH
• genový knockdown MeSH
• inhibiční koncentrace 50 MeSH
• invazivní růst nádoru MeSH
• lidé MeSH
• maligní mezoteliom MeSH
• mezoteliom metabolismus   patologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• myši nahé MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• nádory plic metabolismus   patologie   MeSH
• progrese nemoci MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• tokoferoly farmakologie   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CD24 MeSH
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• tokoferoly MeSH