The major role of mitochondria is to provide cells with energy, but no less important are their roles in responding to various stress factors and the metabolic changes and pathological processes that might occur inside and outside the cells. The post-translational modification of proteins is a fast and efficient way for cells to adapt to ever changing conditions. Phosphorylation is a post-translational modification that signals these changes and propagates these signals throughout the whole cell, but it also changes the structure, function and interaction of individual proteins. In this review, we summarize the influence of kinases, the proteins responsible for phosphorylation, on mitochondrial biogenesis under various cellular conditions. We focus on their role in keeping mitochondria fully functional in healthy cells and also on the changes in mitochondrial structure and function that occur in pathological processes arising from the phosphorylation of mitochondrial proteins.

• Klíčová slova
• disease, kinases, mitochondria, phosphorylation,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, α-tocopherol succinate (α-TOS) and α-tocopherol phosphate (α-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that α-TOS and α-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with α-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by α-TOS may contribute to its known anti-cancer pharmacological activity.

• Klíčová slova
• Cancer Therapy, Computer Modeling, Cytochrome c, Peroxidase, Protein Folding, Vitamin E,
• MeSH
• aktivace enzymů účinky léků   MeSH
• alfa-tokoferol analogy a deriváty   chemie   farmakologie   MeSH
• apoptóza účinky léků   genetika   MeSH
• buněčné linie MeSH
• cytochromy c chemie   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• koně MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši knockoutované MeSH
• peroxidasa chemie   metabolismus   MeSH
• spektrofotometrie MeSH
• terciární struktura proteinů MeSH
• vazba proteinů MeSH
• vazebná místa genetika   MeSH
• vitaminy chemie   metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• alfa-tokoferol MeSH
• alpha-tocopherol phosphate MeSH Prohlížeč
• cytochromy c MeSH
• peroxidasa MeSH
• vitaminy MeSH