Abstract
Mitochondria, once merely considered as the “powerhouse” of cells, as they generate more than 90 % of cellular ATP, are now known to play a central role in many metabolic processes, including oxidative stress and apoptosis. More than 40 known human diseases are the result of excessive production of reactive oxygen species (ROS), bioenergetic collapse and dysregulated apoptosis. Mitochondria are the main source of ROS in cells, due to the activity of the respiratory chain. In normal physiological conditions, ROS generation is limited by the anti-oxidant enzymatic systems in mitochondria. However, disregulation of the activity of these enzymes or interaction of respiratory complexes with mitochondriotropic agents may lead to a rise in ROS concentrations, resulting in oxidative stress, mitochondrial permeability transition (MPT) induction and triggering of the apoptotic pathway. ROS concentration is also increased by the activity of amine oxidases located inside and outside mitochondria, with oxidation of biogenic amines and polyamines. However, it should also be recalled that, depending on its concentration, the polyamine spermine can also protect against stress caused by ROS scavenging. In higher organisms, cell signaling pathways are the main regulators in energy production, since they act at the level of mitochondrial oxidative phosphorylation and participate in the induction of the MPT. Thus, respiratory complexes, ATP synthase and transition pore components are the targets of tyrosine kinases and phosphatases. Increased ROS may also regulate the tyrosine phosphorylation of target proteins by activating Src kinases or phosphatases, preventing or inducing a number of pathological states.
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Abbreviations
- MAO:
-
Monoamine oxidase
- AdNT:
-
Adenine nucleotide translocase
- RCI:
-
Respiratory control index
- P/O ratio:
-
Ratio ATP and consumed oxygen
- ROS:
-
Reactive oxygen species
- MPT:
-
Mitochondrial permeability transition
- O ·−2 :
-
Superoxide anion
- RNS:
-
Reactive nitrogen species
- FMN:
-
Flavin mono nucleotide
- CoQH2/CoQ:
-
Cofactor, ubiquinol/ubiquinone ratio
- MnSOD:
-
Mitochondrial superoxide dismutase
- ONOO− :
-
Peroxynitrite
- MAOs:
-
Monoamine oxidases
- FAD:
-
Flavin adenine dinucleotide
- ·NO:
-
Nitric oxide
- mtNOS:
-
Mitochondrial nitric oxide synthase
- MDA:
-
Malondialdehyde
- HNE:
-
Hydroxynonenal
- ALE:
-
Lipoperoxidation
- TPP+ :
-
Triphenylphosphonium
- ΔΨ :
-
Electrical membrane potential
- PTPC:
-
Permeability transition pore complex
- VDAC:
-
Voltage-dependent anion channel
- ANT:
-
Adenine nucleotide translocase
- RTK:
-
Receptor tyrosine kinases
- NRTK:
-
Non-receptor tyrosine kinases
- EGFR:
-
Epidermal growth factor receptor
- SFKs:
-
Src family kinases
- PTPs:
-
Tyrosine phosphatases
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Acknowledgments
The authors would like to thank Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) and the Istituto Pasteur-Fondazione Cenci Bolognetti (EA). This work is dedicated to our dear friend and esteemed colleague, Dr. Giampiero Tempera, Ph.D., who died on 19 in December 2014.
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Grancara, S., Zonta, F., Ohkubo, S. et al. Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation. Amino Acids 47, 869–883 (2015). https://doi.org/10.1007/s00726-015-1964-7
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DOI: https://doi.org/10.1007/s00726-015-1964-7