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Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation

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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

References

  • Adam-Vizi V, Chinopoulos C (2006) Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645

    PubMed  CAS  Google Scholar 

  • Agostinelli E, Arancia G, Vedova LD, Belli F, Marra M, Salvi M, Toninello A (2004) The biological functions of polyamines oxidation products by amine oxidases: perspectives of clinical applications. Amino Acids 27:347–358

    PubMed  CAS  Google Scholar 

  • Agostinelli E, Tempera G, Molinari A, Salvi M, Battaglia V, Toninello A, Arancia G (2007) The physiological role of biogenic amines redox reactions in mitochondria. New perspectives in cancer therapy. Amino Acids 33:175–187

    PubMed  CAS  Google Scholar 

  • Agostinelli E, Tempera G, Viceconte N, Saccoccio S, Battaglia V, Grancara S, Toninello A, Stevanato R (2010) Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids 38:353–368

    PubMed  CAS  Google Scholar 

  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) The molecular biology of the cell, 4th edn. Garland Science, New York

    Google Scholar 

  • Aliev G, Smith MA, Seyidov D, Neal ML, Lamb BT, Nunomura A, Gasimov EK, Vinters HV, Perry G, LaManna JC, Friedland RP (2002) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer’s disease. Brain Pathol 12:21–35

    PubMed  CAS  Google Scholar 

  • Alvarez S, Valdez LB, Zaobornyj T, Boveris A (2003) Oxygen dependence of mitochondrial nitric oxide synthase activity. Biochem Biophys Res Commun 305:771–775

    PubMed  CAS  Google Scholar 

  • Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Moscow) 70:200–214

    CAS  Google Scholar 

  • Armanini D, Fiore C, Mattarello MJ, Bielenberg J, Palermo M (2002) History of the endocrine effects of licorice. Exp Clin Endocrinol Diabetes 110:257–261

    PubMed  CAS  Google Scholar 

  • Azarashvili T, Odinokova I, Bakunts A, Ternovsky V, Krestinina O, Tyynelä J, Saris NE (2014) Potential role of subunit c of F0F1-ATPase and subunit c of storage body in the mitochondrial permeability transition. Effect of the phosphorylation status of subunit c on pore opening. Cell Calcium 55:69–77

    PubMed  CAS  Google Scholar 

  • Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

    PubMed  CAS  Google Scholar 

  • Barja G (1999) Kinetic measurement of mitochondrial oxygen radical production. In: Methods in aging research. CRC press, Boca Raton, pp 533–548

  • Battaglia V, Rossi CA, Colombatto S, Grillo MA, Toninello A (2007) Different behaviour of agmatine in liver mitochondria: inducer of oxidative stress or scavenger of reactive oxygen species? Biochim Biophys Acta 1768:1147–1153

    PubMed  CAS  Google Scholar 

  • Battaglia V, Tibaldi E, Grancara S, Zonta F, Brunati AM, Martinis P, Bragadin M, Grillo MA, Tempera G, Agostinelli E, Toninello A (2012) Effect of peroxides on spermine transport in rat brain and liver mitochondria. Amino Acids 42:741–749

    PubMed  CAS  Google Scholar 

  • Bonaiuto E, Grancara S, Martinis P, Stringaro A, Colone M, Agostinelli E, Macone A, Stevanato R, Vianello F, Toninello A, Di Paolo ML (2015) A novel enzyme with spermine oxidase properties in bovine liver mitochondria: identification and kinetic characterization. Free Radic Biol Med. doi:10.1016/j.freeradbiomed.2015.01.001

  • Boveris A (1984) Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. Methods Enzymol 105:429–435

    PubMed  CAS  Google Scholar 

  • Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716

    PubMed Central  PubMed  CAS  Google Scholar 

  • Boveris A, Costa LE, Cadenas E (1999) The mitochondrial production of oxygen radicals and cellular aging. In: Cadenas E, Packer L (eds) Understanding the process of aging: the roles of mitochondria, free radicals, and antioxidants. Marcel Dekker, Inc., New York, pp 1–16

    Google Scholar 

  • Brown GC, Borutaite V (2004) Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta 1658:44–49

    PubMed  CAS  Google Scholar 

  • Butow RA, Avadhani NG (2004) Mitochondrial signaling: the retrograde response. Mol Cell 14:1–15

    PubMed  CAS  Google Scholar 

  • Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29:222–230

    PubMed  CAS  Google Scholar 

  • Cao G, Sofic E, Prior RL (1997a) Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships. Free Radic Biol Med 22:749–760

    PubMed  CAS  Google Scholar 

  • Cao G, Sofic E, Prior RL (1997b) Antioxidant and prooxidant behaviour of flavonoids: structure–activity relationships. Free Radic Biol Med 22:749–760

    PubMed  CAS  Google Scholar 

  • Cao X, Zhu H, Ali-Osman F, Lo HW (2011) EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis. Mol Cancer 10:26

    PubMed Central  PubMed  CAS  Google Scholar 

  • Carafoli E (1982) The regulation of intracellular calcium. Adv Exp Med Biol 151:461–472

    PubMed  CAS  Google Scholar 

  • Carafoli E (2003) Historical review: mitochondria and calcium: ups and downs of an unusual relationship. Trends Biochem Sci 28:175–181

    PubMed  CAS  Google Scholar 

  • Carafoli E, Crompton M (1978) The regulation of intracellular calcium. Curr Top Membr Trans 10:151–216

    CAS  Google Scholar 

  • Carelli V, Chan DC (2014) Mitochondrial DNA: impacting central and peripheral nervous systems. Neuron 84:1126–1142

    PubMed  CAS  Google Scholar 

  • Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem 217:383–393

    PubMed  CAS  Google Scholar 

  • Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605

    PubMed  CAS  Google Scholar 

  • Chen LB (1988) Mitochondrial membrane potential in living cells. Annu Rev Cell Biol 4:155–181

    PubMed  CAS  Google Scholar 

  • Cochemè HM, Kelso GF, James AM, Ross MF, Trnka J, Mahendiran T, Asin-Cayuela J, Blaikie FH, Manas AR, Porteous CM, Adlam VJ, Smith RA, Murphy MP (2007) Mitochondrial targeting of quinones: therapeutic implications. Mitochondrion 7(Suppl. 1):S94–S102

    PubMed  Google Scholar 

  • Crompton M, Capano M, Carafoli E (1976) Respiration-dependent efflux of magnesium ions from heart mitochondria. Biochem J 154:735–742

    PubMed Central  PubMed  CAS  Google Scholar 

  • Cuozzo JW, Kaiser CA (1999) Competition between glutathione and protein thiols for disulphide-bond formation. Nat Cell Biol 1:130–135

    PubMed  CAS  Google Scholar 

  • Dalla Via L, Di Noto V, Siliprandi D, Toninello A (1996) Spermine binding to liver mitochondria. Biochem Biophys Acta 1284:247–253

    PubMed  Google Scholar 

  • Dalla Via L, Di Noto V, Toninello A (1999) Binding of spermidine and putrescine to energized liver mitochondria. Arch Biochem Biophys 365:231–238

    PubMed  CAS  Google Scholar 

  • Dennis JW, Laferte S, Waghorne C, Breitman ML, Kerbel RS (1987) Beta 1–6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236:582–585

    PubMed  CAS  Google Scholar 

  • Di Mauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668

    Google Scholar 

  • Di Pancrazio F, Bisetto E, Alverdi V, Mavelli I, Esposito G, Lippe G (2006) Differential steady-state tyrosine phosphorylation of two oligomeric forms of mitochondrial F0F1 ATPsynthase: a structural proteomic analysis. Proteomics 6:921–926

    PubMed  Google Scholar 

  • Dong Sun L, Sang Han L (2001) Genistein, a soy isoflavone, is a potent a-glucosidase inhibitor. FEBS Lett 501:84–86

    Google Scholar 

  • Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    PubMed  Google Scholar 

  • Du Y, Bales KR, Dodel RC, Hamilton-Byrd E, Horn JW, Czilli DL, Simmons LK, Ni B, Paul SM (1997) Activation of a caspase 3-related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons. Proc Natl Acad Sci USA 94:11657–11662

    PubMed Central  PubMed  CAS  Google Scholar 

  • Duke RC, Ojcius DM, Young JD (1996) Cell suicide in health and disease. Sci Am 275:80–87

    PubMed  CAS  Google Scholar 

  • Ernster L, Kuylenstierna B (1969) Structure, composition and function of mitochondrial membranes. In: Ernster L (ed) Mitochondria structure and function. Academic Press, London, pp 5–31

    Google Scholar 

  • Fantin VR, Leder P (2004) F16, a mitochondriotoxic compound, triggers apoptosis or necrosis depending on the genetic background of the target carcinoma cell. Cancer Res 64:329–336

    PubMed  CAS  Google Scholar 

  • Fantin VR, Leder P (2006) Mitochondriotoxic compounds for cancer therapy. Oncogene 25:4787–4797

    PubMed  CAS  Google Scholar 

  • Fantin VR, Berardi MJ, Scorrano L, Korsmeyer SJ, Leder P (2002) A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. Cancer Cell 2:29–42

    PubMed  CAS  Google Scholar 

  • Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434

    PubMed  CAS  Google Scholar 

  • Feng J, Zhu M, Schaub MC, Gehrig P, Roschitzki B, Lucchinetti E, Zaugg M (2008) Phosphoproteome analysis of isoflurane-protected heart mitochondria: phosphorylation of adenine nucleotide translocator-1 on Tyr194 regulates mitochondrial function. Cardiovasc Res 80:20–29

    PubMed  CAS  Google Scholar 

  • Firuzi O, Lacanna A, Petrucci R, Marrosu G, Saso L (2005) Evaluation of the antioxidant activity of flavonoids by “ferric reducing antioxidant power” assay and cyclic voltammetry. Biochim Biophys Acta 1721:174–184

    PubMed  CAS  Google Scholar 

  • Fonyo A, Ligeti E, Palmieri F, Quagliariello E (1975) Carrier-mediated tran sport of phosphate in mitochondria. In: Gardos G, Szasz I (eds) Biomembranes, structure and function. Elsevier, North Holland, pp 287–306

    Google Scholar 

  • Forman HJ, Kennedy JA (1974) Role of superoxide radical in mitochondrial dehydrogenase reactions. Biochem Biophys Res Commun 60:1044–1050

    PubMed  CAS  Google Scholar 

  • Forman HJ, Davies KJ, Ursini F (2014) How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med 66:24–35

    PubMed  CAS  Google Scholar 

  • Frei B, Higdon JV (2003) Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr 133:3275S–3284S

    PubMed  CAS  Google Scholar 

  • Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T (1980) Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. J Neurol Sci 47:117–133

    PubMed  CAS  Google Scholar 

  • Giannoni E, Chiarugi P (2014) Redox circuitries driving Src regulation. Antioxid Redox Signal 20:2011–2025

    PubMed  CAS  Google Scholar 

  • Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabó I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892

    PubMed Central  PubMed  CAS  Google Scholar 

  • Goldenthal MJ, Marín-García J (2004) Mitochondrial signaling pathways: a receiver/integrator organelle. Mol Cell Biochem 262:1–16

    PubMed  CAS  Google Scholar 

  • Goldwyn S, Lazinsky A, Wie H (2000) Promotion of health by soy isoflavones: efficacy, benefit and concerns. Drug Metab Drug Interac 17:261–289

    CAS  Google Scholar 

  • Golstein P (1998) Cell death in us and others. Science 281:1283

    PubMed  CAS  Google Scholar 

  • Görlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal 8:1391–1418

    PubMed  Google Scholar 

  • Grancara S, Battaglia V, Martinis P, Viceconte N, Agostinelli E, Toninello A, Deana R (2012) Mitochondrial oxidative stress induced by Ca2+ and monoamines: different behaviour of liver and brain mitochondria in undergoing permeability transition. Amino Acids 42:751–759

    PubMed  CAS  Google Scholar 

  • Grancara S, Martinis P, Manente S, García-Argáez AN, Tempera G, Bragadin M, Dalla Via L, Agostinelli E, Toninello A (2014) Bidirectional fluxes of spermine across the mitochondrial membrane. Amino Acids 46:671–679

    PubMed  CAS  Google Scholar 

  • Green DR, Reed JC (1988) Mitochondria and apoptosis. Science 281:1309–1311

    Google Scholar 

  • Gringeri E, Carraro A, Tibaldi E, D’Amico FE, Mancon M, Toninello A, Pagano MA, Vio C, Cillo U, Brunati AM (2009) Lyn-mediated mitochondrial tyrosine phosphorylation is required to preserve mitochondrial integrity in early liver regeneration. Biochem J 425:401–412

    PubMed  Google Scholar 

  • Gruters RA, Neefjes JJ, Tersmette M, de Goede REY, Tulp A, Huisman HG, Miedema F, Ploegh HL (1987) Interference with HIV induced syncytium formation and viral infectivity by inhibitors of trimming glucosidase. Nature 330:74–77

    PubMed  CAS  Google Scholar 

  • Gunter TE, Gunter KK (2001) Uptake of calcium by mitochondria: transport and possible function. IUBMB Life 52:197–204

    PubMed  CAS  Google Scholar 

  • Gunter TE, Buntinas L, Sparagna G, Eliseev R, Gunter K (2000) Mitochondrial calcium transport: mechanisms and functions. Cell Calcium 28:285–296

    PubMed  CAS  Google Scholar 

  • Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423:456–461

    PubMed  CAS  Google Scholar 

  • Ha HC, Sirisoma NS, Kuppusamy P, Zweier JL, Woster PM, Casero RA Jr (1998) The natural polyamine spermine functions directly as a free radical scavenger. Proc Natl Acad Sci USA 95:11140–11145

    PubMed Central  PubMed  CAS  Google Scholar 

  • Hackenbrock CR (1968) Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci USA 61:598–605

    PubMed Central  PubMed  CAS  Google Scholar 

  • Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003) Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278:5557–5563

    PubMed  CAS  Google Scholar 

  • Hare ML (1928) Tyramine oxidase: a new enzyme system in liver. Biochem J 22:968–979

    PubMed Central  PubMed  CAS  Google Scholar 

  • Harrington JL, Murphy E (2015) The mitochondrial calcium uniporter: mice can live and die without it. J Mol Cell Cardiol 78:46–53

    PubMed  CAS  Google Scholar 

  • Hauptmann N, Grimsby J, Shih JC, Cadenas E (1996) The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA. Arch Biochem Biophys 335:295–304

    PubMed  CAS  Google Scholar 

  • Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596–610

    PubMed  CAS  Google Scholar 

  • Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88

    PubMed Central  PubMed  CAS  Google Scholar 

  • Haynes V, Elfering S, Traaseth N, Giulivi C (2004) Mitochondrial nitric-oxide synthase: enzyme expression, characterization, and regulation. J Bioenerg Biomembr 36:341–346

    PubMed  CAS  Google Scholar 

  • Hebert-Chatelain E (2013) Src kinases are important regulators of mitochondrial functions. Int J Biochem Cell Biol 45:90–98

    PubMed  CAS  Google Scholar 

  • Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, Ge Q, Gu TL, Polakiewicz RD, Roesel JL, Chen GZ, Boggon TJ, Lonial S, Fu H, Khuri FR, Kang S, Chen J (2011) Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1is important for cancer metabolism. Mol Cell 44:864–877

    PubMed Central  PubMed  CAS  Google Scholar 

  • Horbinski C, Chu CT (2005) Kinase signaling cascades in the mitochondrion: a matter of life or death. Free Radic Biol Med 38:2–11

    PubMed  CAS  Google Scholar 

  • Horobin RW, Trapp S, Weissig VJ (2007) Mitochondriotropics: a review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria. J Control Release 121:125–136

    PubMed  CAS  Google Scholar 

  • Hüttemann M, Lee I, Samavati L, Yu H, Doan JW (2007) Regulation of mitochondrial oxidative phosphorylation through cell signaling. Biochim Biophys Acta 1773:1701–1720

    PubMed  Google Scholar 

  • Imai H, Nakagawa Y (2003) Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med 34:145–169

    PubMed  CAS  Google Scholar 

  • Jenkins DJ, Taylor RH, Goff DV, Fielden H, Misiewicz JJ, Sarson DL, Bloom SR, Alberti KG (1981) Scope and specificity of acarbose in slowing carbohydrate absorption in man. Diabetes 30:951–954

    PubMed  CAS  Google Scholar 

  • Jovanovic SV, Steenken S, Tosic M, Marjanovic B, Simic MG (1994) Flavonoids as antioxidants. J Am Chem Soc 116:4846–4851

    CAS  Google Scholar 

  • Kabunga P, Lau AK, Phan K, Puranik R, Liang C, Davis RL, Sue CM, Sy RW (2014) Systematic review of cardiac electrical disease in Kearns–Sayre syndrome and mitochondrial cytopathy. Int J Cardiol 181C:303–310

    Google Scholar 

  • Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology 7:153–163

    PubMed  CAS  Google Scholar 

  • Kearns TP, Sayre GP (1958) Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol 60:280–289

    PubMed  CAS  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kerr JF, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy. Cancer 73:2013–2026

    PubMed  CAS  Google Scholar 

  • Kim HR, Won SJ, Fabian C, Kang MG, Szardenings M, Shin MG (2015) Mitochondrial DNA aberrations and pathophysiological implications in hematopoietic diseases, chronic inflammatory diseases, and cancers. Ann Lab Med 35:1–14

    PubMed Central  PubMed  Google Scholar 

  • Klingenberg M (1979) The ADP, ATP shuttle of the mitochondrion. Trends Biochem Sci 4:249–252

    CAS  Google Scholar 

  • Klingenberg M, Winkler E, Huang S (1995) ADP/ATP carrier and uncoupling protein. Methods Enzymol 260:369–389

    PubMed  CAS  Google Scholar 

  • Kudin AP, Bimpong-Buta NY, Vielhaber S, Elger CE, Kunz WS (2004) Characterization of superoxide-producing sites in isolated brain mitochondria. J Biol Chem 279:127–135

    Google Scholar 

  • Kuroki T, Isshiki K, King GL (2003) Oxidative stress: the lead or supporting actor in the pathogenesis of diabetic complications. J Am Soc Nephrol 14:S216–S220

    PubMed  CAS  Google Scholar 

  • La Regina G, Silvestri R, Artico M, Lavecchia A, Novellino E, Befani O, Turini P, Agostinelli E (2007) New pyrrole inhibitors of monoamine oxidase: synthesis, biological evaluation, and structural determinants of MAO-A and MAO-B selectivity. J Med Chem 50:922–931

    PubMed  Google Scholar 

  • Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189

    PubMed  CAS  Google Scholar 

  • LaNoue KF, Schoolwerth AC (1979) Metabolite transport in mitochondria. Annu Rev Biochem 48:871–922

    PubMed  CAS  Google Scholar 

  • Lapidus RG, Sokolove PM (1992) Inhibition by spermine of the inner membrane permeability transition of isolated rat heart mitochondria. FEBS Lett 313:314–318

    PubMed  CAS  Google Scholar 

  • Lapidus RG, Sokolove PM (1993) Spermine inhibition of the permeability transition of isolated rat liver mitochondria: an investigation of mechanism. Arch Biochem Biophys 306:246–253

    PubMed  CAS  Google Scholar 

  • Lapidus RG, Sokolove PM (1994) The mitochondrial permeability transition: interactions of spermine, ADP, and inorganic phosphate. J Biol Chem 269:18931–18936

    PubMed  CAS  Google Scholar 

  • Leber T (1871) Ueber hereditaere und congenital-angelegte Sehnervenleiden. Arch Ophthalmol 17:249–291

    Google Scholar 

  • Lefebvre J, Muharram G, Leroy C, Kherrouche Z, Montagne R, Ichim G, Tauszig-Delamasure S, Chotteau-Lelievre A, Brenner C, Mehlen P, Tulasne D (2013) Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity. Cell Death Dis 4:e871

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lewandrowski U, Sickmann A, Cesaro L, Brunati AM, Toninello A, Salvi M (2008) Identification of new tyrosine phosphorylated proteins in rat brain mitochondria. FEBS Lett 582:1104–1110

    PubMed  CAS  Google Scholar 

  • Liu Y, Fiskum G, Schubert D (2002) Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem 80:780–787

    PubMed  CAS  Google Scholar 

  • Loschen G, Flohé L, Chance B (1971) Respiratory chain linked H2O2 production in pigeon heart mitochondria. FEBS Lett 18:261–264

    PubMed  CAS  Google Scholar 

  • Loschen G, Azzi A, Richter C, Flohé L (1974) Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42:68–72

    PubMed  CAS  Google Scholar 

  • MacDonald MJ, Fahien LA, Brown LJ, Hasan NM, Buss JD, Kendrick MA (2005) Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion. Am J Physiol Endocrinol Metab 288:E1–E15

    PubMed  CAS  Google Scholar 

  • Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–129

    PubMed  CAS  Google Scholar 

  • Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by chemi-osmotic type of mechanism. Nature 191:144–148

    PubMed  CAS  Google Scholar 

  • Muller F (2000) The nature and mechanism of superoxide production by the electron transport chain. J Am Aging Assoc 23:227–253

    PubMed Central  PubMed  CAS  Google Scholar 

  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    PubMed Central  PubMed  CAS  Google Scholar 

  • Murphy MP, Smith RA (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629–656

    PubMed  CAS  Google Scholar 

  • Naqui A, Chance B, Cadenas E (1986) Reactive oxygen intermediates in biochemistry. Annu Rev Biochem 55:137–166

    PubMed  CAS  Google Scholar 

  • Navarro A, Boveris A (2008) Mitochondrial nitric oxide synthase, mitochondrial brain dysfunction in aging, and mitochondria-targeted antioxidants. Adv Drug Deliv Rev 60:1534–1544

    PubMed  CAS  Google Scholar 

  • Newmeyer DD, Ferguson-Miller S (2003) Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112:481–490

    PubMed  CAS  Google Scholar 

  • Nicholls DG, Crompton M (1980) Mitochondrial calcium transport. FEBS Lett 111:261–268

    PubMed  CAS  Google Scholar 

  • Ogura M, Yamaki J, Homma MK, Homma Y (2012) Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components. Biochem J 447:281–289

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ogura M, Yamaki J, Homma MK, Homma Y (2014) Phosphorylation of flotillin-1 by mitochondrial c-Src is required to prevent the production of reactive oxygen species. FEBS Lett 588:2837–2843

    PubMed  CAS  Google Scholar 

  • Packer MA, Porteous CM, Murphy MP (1996) Superoxide production by mitochondria in the presence of nitric oxide forms peroxynitrite. Biochem Mol Biol Int 40:527–534

    PubMed  CAS  Google Scholar 

  • Pagliarini DJ, Dixon JE (2006) Mitochondrial modulation: reversible phosphorylation takes center stage? Trends Biochem Sci 31:26–34

    PubMed  CAS  Google Scholar 

  • Pal A, Fontanilla D, Gopalakrishnan A, Chae YK, Markley JL, Ruoho AE (2012) The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol 682:12–20

    PubMed Central  PubMed  CAS  Google Scholar 

  • Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S (2004) Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci USA 101:7630–7635

    PubMed Central  PubMed  CAS  Google Scholar 

  • Palmieri F, Klingenberg M (1979) Direct methods for measuring metabolite transport and distribution in mitochondria. Methods Enzymol 56:279–301

    PubMed  CAS  Google Scholar 

  • Pantic B, Trevisan E, Citta A, Rigobello MP, Marin O, Bernardi P, Salvatori S, Rasola A (2013) Myotonic dystrophy protein kinase (DMPK) prevents ROS-induced cell death by assembling a hexokinase II-Src complex on the mitochondrial surface. Cell Death Dis 4:e858

    PubMed Central  PubMed  CAS  Google Scholar 

  • Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16:481–488

    PubMed  CAS  Google Scholar 

  • Peterson G (1995) Evaluation of the biochemical targets of genistein in tumor cells. J Nutr 125:S784–S789

    Google Scholar 

  • Pfeiffer DR, Gunter TE, Eliseev R, Broekemeier KM, Gunter KK (2001) Release of Ca2+ from mitochondria via the saturable mechanisms and the permeability transition. IUBMB Life 52:205–212

    PubMed  CAS  Google Scholar 

  • Plotnikov EY, Morosanova MA, Pevzner IB, Zorova LD, Manskikh VN, Pulkova NV, Galkina SI, Skulachev VP, Zorov DB (2013) Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection. Proc Natl Acad Sci USA 110:E3100–E3108

    PubMed Central  PubMed  CAS  Google Scholar 

  • Polkowski K, Mazurek AP (2000) Biological properties of genistein. A review of in vitro and in vivo effects. Acta Pol Pharm 57:135–155

    PubMed  CAS  Google Scholar 

  • Puskin JS, Gunter TE, Gunter KK, Russell PR (1976) Evidence for more than one Ca2+ transport mechanism in mitochondria. Biochemistry 15:3834–3842

    PubMed  CAS  Google Scholar 

  • Radi R, Turrens JF, Chang LY, Bush KM, Crapo JD, Freeman BA (1991) Detection of catalase in rat heart mitochondria. J Biol Chem 266:22028–22034

    PubMed  CAS  Google Scholar 

  • Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25:502–508

    PubMed  CAS  Google Scholar 

  • Rhee SG, Kang SW, Chang TS, Jeong W, Kim K (2001) Peroxiredoxin, a novel family of peroxidases. IUBMB Life 52:35–41

    PubMed  CAS  Google Scholar 

  • Rich P (2003) Chemiosmotic coupling: the cost of living. Nature 421:583

    PubMed  CAS  Google Scholar 

  • Rizzuto R, Bernardi P, Pozzan T (2000) Mitochondria as all-round players of the calcium game. J Physiol 529(Pt 1):37–47

    PubMed Central  PubMed  CAS  Google Scholar 

  • Rottenberg H, Scarpa A (1974) Calcium uptake and membrane potential in mitochondria. Biochemistry 13:4811–4817

    PubMed  CAS  Google Scholar 

  • Rubattu S, Pagliaro B, Pierelli G, Santolamazza C, Castro SD, Mennuni S, Volpe M (2014) Pathogenesis of target organ damage in hypertension: role of mitochondrial oxidative stress. Int J Mol Sci 16:823–839

    PubMed Central  PubMed  Google Scholar 

  • Salvesen GS, Dixit VM (1999) Caspase activation: the induced proximity model. Proc Natl Acad Sci USA 96:10964–10967

    PubMed Central  PubMed  CAS  Google Scholar 

  • Salvi M, Toninello A (2004) Effects of polyamines on mitochondrial Ca2+ transport. Biochim Biophys Acta 1661:113–124

    PubMed  CAS  Google Scholar 

  • Salvi M, Brunati AM, Bordin L, La Rocca N, Clari G, Toninello A (2002a) Characterization and location of Src-dependent tyrosine phosphorylation in rat brain mitochondria. Biochim Biophys Acta 1589:181–195

    PubMed  CAS  Google Scholar 

  • Salvi M, Brunati AM, Clari G, Toninello A (2002b) Interaction of genistein with the mitochondrial electron transport chain results in opening of the membrane transition pore. Biochim Biophys Acta 1556:187–196

    PubMed  CAS  Google Scholar 

  • Salvi M, Stringaro A, Brunati AM, Agostinelli E, Arancia G, Clari G, Toninello A (2004) Tyrosine phosphatase activity in mitochondria: presence of Shp-2 phosphatase in mitochondria. Cell Mol Life Sci 61:2393–2404

    PubMed  CAS  Google Scholar 

  • Salvi M, Brunati AM, Toninello A (2005a) Tyrosine phosphorylation in mitochondria: a new frontier in mitochondrial signaling. Free Radic Biol Med 38:1267–1277

    PubMed  CAS  Google Scholar 

  • Salvi M, Fiore C, Battaglia V, Palermo M, Armanini D, Toninello A (2005b) Carbenoxolone induces oxidative stress in liver mitochondria, which is responsible for transition pore opening. Endocrinology 146:2306–2312

    PubMed  CAS  Google Scholar 

  • Salvi M, Battaglia V, Brunati AM, La Rocca N, Tibaldi E, Pietrangeli P, Marcocci L, Mondovì B, Rossi CA, Toninello A (2007a) Catalase takes part in rat liver mitochondria oxidative stress defense. J Biol Chem 282:24407–24415

    PubMed  CAS  Google Scholar 

  • Salvi M, Morrice NA, Brunati AM, Toninello A (2007b) Identification of the flavoprotein of succinate dehydrogenase and aconitase as in vitro mitochondrial substrates of Fgr tyrosine kinase. FEBS Lett 581:5579–5585

    PubMed  CAS  Google Scholar 

  • Sanderson TH, Mahapatra G, Pecina P, Ji Q, Yu K, Sinkler C, Varughese A, KumarR Bukowski MJ, Tousignant RN, Salomon AR, Lee I, Hüttemann M (2013) Cytochrome c is tyrosine 97 phosphorylated by neuroprotective insulin treatment. PLoS One 8:e78627

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sava IG, Battaglia V, Rossi CA, Salvi M, Toninello A (2006) Free radical scavenging action of the natural polyamine spermine in rat liver mitochondria. Free Radic Biol Med 41:1272–1281

    PubMed  CAS  Google Scholar 

  • Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212

    PubMed  CAS  Google Scholar 

  • Scheffler IE (2008) Mitochondrial mutations and disease. In: Scheffler IE (ed) Mitochondria, 2nd edn. Wiley, Hoboken, pp 345–416

    Google Scholar 

  • Schon EA, DiMauro S, Hirano M (2012) Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 13:878–890

    PubMed Central  PubMed  CAS  Google Scholar 

  • Schwartzman RA, Cidlowski LA (1993) Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev 14:133–151

    PubMed  CAS  Google Scholar 

  • Shan C, Kang HB, Elf S, Xie J, Gu TL, Aguiar M, Lonning S, Hitosugi T, ChungTW Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, Fan J (2014) Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem 289:21413–21422

    PubMed  Google Scholar 

  • Sheu SS, Nauduri D, Anders MW (2006) Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim Biophys Acta 1762:256–265

    PubMed  CAS  Google Scholar 

  • Slater EC (1953) Mechanism of phosphorylation in the respiratory chain. Nature 172:975–978

    PubMed  CAS  Google Scholar 

  • Sparagna GC, Gunter KK, Sheu SS, Gunter TE (1995) Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J Biol Chem 270:27510–27515

    PubMed  CAS  Google Scholar 

  • Stefanova NA, Muraleva NA, Skulachev VP, Kolosova NG (2014) Alzheimer’s disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1. J Alzheimers Dis 38:681–694

    PubMed  CAS  Google Scholar 

  • Stevanato R, Cardillo S, Braga M, De Iuliis A, Battaglia V, Toninello A, Agostinelli E, Vianello F (2011) Preliminary kinetic characterization of a copper amine oxidase from rat liver mitochondria matrix. Amino Acids 40:713–720

    PubMed  CAS  Google Scholar 

  • Susin SA, Zamzami N, Kroemer G (1998) Mitochondria as regulators of apoptosis, doubt no more. Biochim Biophys Acta 1366:151–165

    PubMed  CAS  Google Scholar 

  • Szabó C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6:662–680

    PubMed  Google Scholar 

  • Tabor H, Tabor CW (1964) Spermidine, spermine, and related amines. Pharmacol Rev 16:245–300

    PubMed  CAS  Google Scholar 

  • Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    PubMed  CAS  Google Scholar 

  • Tibaldi E, Brunati AM, Massimino ML, Stringaro A, Colone M, Agostinelli E, Arancia G, Toninello A (2008) Src-Tyrosine kinases are major agents in mitochondrial tyrosine phosphorylation. J Cell Biochem 104:840–849

    PubMed  CAS  Google Scholar 

  • Toninello A, Miotto G, Siliprandi D, Siliprandi N, Garlid KD (1988) On the mechanism of spermine transport in liver mitochondria. J Biol Chem 263:19407–19411

    PubMed  CAS  Google Scholar 

  • Toninello A, Dalla Via L, Siliprandi D, Garlid KD (1992) Evidence that spermine, spermidine, and putrescine are transported electrophoretically in mitochondria by a specific polyamine uniporter. J Biol Chem 267:18393–18397

    PubMed  CAS  Google Scholar 

  • Toninello A, Dalla Via L, Stevanato R, Yagisawa S (2000) Kinetics and free energy profiles of spermine transport in liver mitochondria. Biochemistry 39:324–331

    PubMed  CAS  Google Scholar 

  • Toninello A, Salvi M, Mondovì B (2004) Interaction of biologically active amines with mitochondria and their role in the mitochondrial-mediated pathway of apoptosis. Curr Med Chem 11:2349–2374

    PubMed  CAS  Google Scholar 

  • Torchilin VP (2006) Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu Rev Biomed Eng 8:343–375

    PubMed  CAS  Google Scholar 

  • Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344

    PubMed Central  PubMed  CAS  Google Scholar 

  • Valente S, Tomassi S, Tempera G, Saccoccio S, Agostinelli E, Mai A (2011) Novel reversible monoamine oxidase a inhibitors: highly potent and selective 3-(1h-pyrrol-3-yl)-2-oxazolidinones. J Med Chem 54:8228–8232

    PubMed  CAS  Google Scholar 

  • Voet D, Voet JG (2004) Electron transport and oxidative phosphorylation. Biochemistry, 3rd edn. Wiley, USA, pp 797–842

    Google Scholar 

  • Vogt S, Riehl A, Koch V, Kadenbach B (2007) Regulation of oxidative phosphorylation by inhibition of its enzyme complexes via reversible phosphorylation. Curr Enzym Inhib 3:189–206

    CAS  Google Scholar 

  • Votyakova TV, Reynolds IJ (2001) DeltaPsi(m)-dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem 79:266–277

    PubMed  CAS  Google Scholar 

  • Wallace DC (1997) Mitochondrial DNA in aging and diseases. Sci Am 227:40–47

    Google Scholar 

  • Weissig V (2005) Targeted drug delivery to mammalian mitochondria in living cells. Expert Opin Drug Deliv 2:89–102

    PubMed  CAS  Google Scholar 

  • WHO, World Health Organization (1999) Radix glycyrrhizae. In: Monographs on selected medicinal plants, vol 1. WHO, Geneva, pp 183–194

  • Winterbourn CC (2008) Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol 4:278–286

    PubMed  CAS  Google Scholar 

  • Winterbourn CC, French JK, Claridge RF (1978) Superoxide dismutase as an inhibitor of reactions of semiquinone radicals. FEBS Lett 94:269–272

    PubMed  CAS  Google Scholar 

  • Wohlrab H (2005) The human mitochondrial transport protein family: identification and protein regions significant for transport function and substrate specificity. Biochim Biophys Acta 1709:157–168

    PubMed  CAS  Google Scholar 

  • Yen K, Lee C, Mehta H, Cohen P (2013) The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol 50:R11–R19

    PubMed Central  PubMed  CAS  Google Scholar 

  • Yoshida S, Tsutsumi S, Muhlebach G, Sourbier C, Lee MJ, Lee S, Vartholomaiou E, Tatokoro M, Beebe K, Miyajima N, Mohney RP, Chen Y, Hasumi H, Xu W, Fukushima H, Nakamura K, Koga F, Kihara K, Trepel J, Picard D, Neckers L (2013) Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Proc Natl Acad Sci USA 110:E1604–E1612

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, Susin SA, Petit PX, Mignotte B, Kroemer G (1995) Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med 182:367–377

    PubMed  CAS  Google Scholar 

  • Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez Monterrey I, Castedo M, Kroemer G (1996) Mitochondrial control of nuclear apoptosis. J Exp Med 183:1533–1544

    PubMed  CAS  Google Scholar 

  • Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zheng H, Li S, Hsu P, Qu CK (2013) Induction of a tumor-associated activating mutation in protein tyrosine phosphatase Ptpn11 (Shp2) enhances mitochondrial metabolism, leading to oxidative stress and senescence. J Biol Chem 288:25727–25738

    PubMed Central  PubMed  CAS  Google Scholar 

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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.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padova, Viale U. Bassi 58B, 35131, Padua, Italy

    Silvia Grancara & Antonio Toninello

  2. Department of Molecular Medicine, University of Padova, Viale G. Colombo 3, 35131, Padua, Italy

    Francesca Zonta & Anna Maria Brunati

  3. “A. Rossi Fanelli” Department of Biochemical Sciences, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome “La Sapienza”, Rome, Italy

    Shinji Ohkubo & Enzo Agostinelli

  4. Institutes of Biology and Molecular Pathology, Consiglio Nazionale delle Ricerche (CNR), P.le Aldo Moro 5, 00185, Rome, Italy

    Shinji Ohkubo & Enzo Agostinelli

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  1. Silvia Grancara
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  2. Francesca Zonta
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Correspondence to Antonio Toninello.

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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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