Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.
- MeSH
- energetický metabolismus MeSH
- ethery metabolismus MeSH
- glycerolfosfátdehydrogenasa * genetika metabolismus MeSH
- lidé MeSH
- mitochondrie * enzymologie MeSH
- myši MeSH
- nádory * enzymologie patologie MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s. During the last 15 years, its popularity increased due to epidemiological evidence, that metformin administration reduces incidence of cancer. However, despite the ongoing effort of many researchers, the molecular mechanisms underlying antihyperglycemic or antineoplastic action of metformin remain elusive. Most frequently, metformin is associated with modulation of mitochondrial metabolism leading to lowering of blood glucose or activation of antitumorigenic pathways. Here we review the reported effects of metformin on mitochondrial metabolism and their potential relevance as effective molecular targets with beneficial therapeutic outcome.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- diabetes mellitus 2. typu farmakoterapie genetika metabolismus patologie MeSH
- glycerolfosfátdehydrogenasa genetika metabolismus MeSH
- hyperglykemie farmakoterapie genetika metabolismus patologie MeSH
- hypoglykemika terapeutické užití MeSH
- lidé MeSH
- metformin terapeutické užití MeSH
- mitochondrie účinky léků genetika metabolismus MeSH
- nádory genetika metabolismus patologie prevence a kontrola MeSH
- oxidativní fosforylace MeSH
- protein-serin-threoninkinasy genetika metabolismus MeSH
- proteinkinasy aktivované AMP genetika metabolismus MeSH
- reaktivní formy kyslíku antagonisté a inhibitory metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- respirační komplex I genetika metabolismus MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is not included in the traditional textbook schemes of the respiratory chain, reflecting the fact that it is a non-standard, tissue-specific component of mammalian mitochondria. But despite its very simple structure, mGPDH is a very important enzyme of intermediary metabolism and as a component of glycerophosphate shuttle it functions at the crossroads of glycolysis, oxidative phosphorylation and fatty acid metabolism. In this review we summarize the present knowledge on the structure and regulation of mGPDH and discuss its metabolic functions, reactive oxygen species production and tissue and organ specific roles in mammalian mitochondria at physiological and pathological conditions.
- MeSH
- alosterická regulace MeSH
- glycerolfosfátdehydrogenasa genetika fyziologie MeSH
- glykolýza MeSH
- lidé MeSH
- mastné kyseliny metabolismus MeSH
- mitochondrie enzymologie MeSH
- orgánová specificita MeSH
- oxidativní fosforylace MeSH
- reaktivní formy kyslíku metabolismus MeSH
- sukcinátdehydrogenasa metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
In our chronic experiments (over several months), the activity and protein amount of glycerol-3-phosphate dehydrogenase (GPDH) in mitochondria isolated from the liver of adult male and female inbred Lewis strain euthyroid (EU), hyperthyroid (TH), and hypothyroid (HY) rats were analyzed by biochemical and Western blot methods. The TH status was induced by intraperitoneal injections of 3,3',5-triiodo- L-thyronine and the HY status with 0.05% solution of methimazole in drinking water. The TH status led to a significant increase and the HY status to a significant decrease of enzyme activity and protein amount in both male and female animals. These changes were, however, more pronounced in females. The EU and TH female rats also showed a significantly higher activity and the TH female rats showed also a significantly higher enzyme amount in comparison with males, while the HY rats showed low levels in both sexes. The glycerol-3-phosphate-dependent oxygen consumption of freshly isolated rat liver mitochondria from the TH animals was higher in comparison with the EU animals and it was activated by idebenone, a synthetic analogue of coenzyme Q, in both the EU and TH rats. Measurements of serum thyroid hormone levels and analysis of anatomical parameters (relative heart and thyroid gland weights) confirmed that our procedures inducing the TH and HY states are efficient and reliable and that determination of GPDH can serve as an additional criterion for the evaluation of the thyroid hormone status.
- MeSH
- exprese genu MeSH
- glycerolfosfátdehydrogenasa genetika metabolismus MeSH
- hormony štítné žlázy krev MeSH
- hypertyreóza enzymologie genetika metabolismus MeSH
- hypotyreóza enzymologie genetika metabolismus MeSH
- jaterní mitochondrie enzymologie metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- potkani inbrední LEW MeSH
- spotřeba kyslíku MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Sturgeon and paddlefish (Acipenseriformes), the source of roe consumed as caviar, are a unique and commercially valuable group of ancient fishes. In this study, comparative proteomics was used to analyze protein profiles of spermatozoa from five sturgeon species and one paddlefish: Siberian sturgeon (Acipenser baerii), sterlet (A. ruthenus), Russian sturgeon (A. gueldenstaedtii), starry sturgeon (A. stellatus), beluga (Huso huso), and Mississippi paddlefish (Polyodon spathula). Protein profiles of spermatozoa were determined by isoelectric focusing and two-dimensional electrophoresis (2-DE) high-resolution gels. The peptides, previously selected by 2-DE analysis as potentially species-specific, were obtained by "in-gel" tryptic digestion, followed by matrix-associated laser desorption/ionization time-of-flight/mass spectrometry (MALDI-TOF/MS). Among the 23 protein spots selected, 14 were identified as isoforms of enolase B present in all species, but with different isoelectric points or molecular mass. Exceptions were A. ruthenus and H. huso, species with a close phylogenetic relationship. Glycerol-3-phosphate dehydrogenase was detected exclusively in P. spathula. Phosphoglycerate kinase was detected only in A. ruthenus and H. huso, and 3 additional proteins (fructose bisphosphate aldolase A-2, glycogen phosphorylase type IV and glyceraldehyde-3-phosphate dehydrogenase) were found exclusively in A. gueldenstaedtii and H. huso. This study points to the application of proteomics for differential characterization and comparative studies of acipenseriform species at the molecular level.
- MeSH
- 2D gelová elektroforéza metody MeSH
- aldolasa genetika metabolismus MeSH
- biologické markery metabolismus MeSH
- druhová specificita MeSH
- fosfoglycerátkinasa genetika metabolismus MeSH
- fosfopyruváthydratasa genetika metabolismus MeSH
- glycerolfosfátdehydrogenasa genetika metabolismus MeSH
- isoelektrická fokusace metody MeSH
- izoenzymy genetika metabolismus MeSH
- peptidové mapování metody MeSH
- peptidy genetika metabolismus MeSH
- proteomika metody MeSH
- ryby klasifikace genetika metabolismus MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice metody MeSH
- spermie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Geografické názvy
- Mississippi MeSH
- Sibiř MeSH
