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Mitochondrial aging – Metabolism and longevity Part I

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011.

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Mitochondrial aging – Metabolism and longevity Part I

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 23 Mitochondrialaging –Metabolism and longevityPart I

  3. Genes encoded by mtDNA Anergia Myoclonus P T F Ataxia Myopathy V E Cyt b Cardiomyopathy Respiratory deficiency 12S ND6 Cardiopathy FBSN 16S Chorea LHON ND5 Deafness MELAS L Human mtDNA 16,569 bp L ND1 Diabetes MERRF S H I Dystonia MILS ? M Q ND4 ND2 Encephalopathy NARP Induced deafness PEO W ND3 A LHON: Leber’s hereditary optic neuropathy MELAS: Mitochondrial encephalomyopathy, lactic acidosis,and stroke-like episodes PEO: Progressive external ophthalmoplegia MELAS: Mitochondrialencephalomyopathy,lactic acidosis and stroke-like episodes MERF: Mycoclorusepilepsywithragged-redfibers FBSN: Familial bilateral striatal necrosis LHON: Leber’s hereditary optic neuropathy MILS: Maternally-inherited Leigh syndrome NARP: Neuropathy, ataxia, and retinitis pigmentosa PEO: Progressive external ophthalmoplegia N R COX III COX I C Y ATPase 8/6 G COX II S D K

  4. Characteristics of mitochondria and mtDNA • Variousnumber and size, dynamicstructures (budding, fusion, fission) • Highmetabolicactivity, intracellularpower house, major source and target of ROS • Extranuclear, doublestranded, closed, circularmtDNA, itslength is 16,569 bp • mtDNAEncodes 37 genes, 2 rRNAs, 22 tRNAs, 13 respiratorychainpolypeptides

  5. Mitochondrial DNA replicationfork OH Initiationfactors RNA Polymerase mtTFA mtTFB1 mtTFB2 mtDNA Additionalactivities Priming RNaseH1/5’-3’ Exonuclease Ligase III Polymerase OL mtSSB Topoisomerase Twinkle

  6. Reasons of mitochondrialvulnerability • Extremeeconomy of codingsequences (minimalnon-coding DNA, no intron) • Notprotectedbyhistones • mtDNArepairmechanismsare less efficient • mtDNAmutationrate is 10× greaterthangDNA

  7. Reason and evidence ofmitochondrial aging • Superoxide (ROS) leak is 0.1% inmitochondria • SOD and co-enzyme Q levelsaffectlife-span • Cardiolipinleveldecreaseswithage

  8. mtDNA damage and hospital admission 600 16 COX deficiency Hospital admission/ 105 population % accumulation of mtDNA damage 14 Hospital admissions 500 12 400 10 300 8 6 200 4 100 2 0 0 1 2 3 4 5 6 7 8 Age (decade)

  9. Organ / tissue specific diseasesof mt origin Nervoussystem: Seizures, spasms, developmentaldelays, deafness, dementia, stroke (oftenbeforeage 40), visualsystemdefects, poorbalance, problemswithperipherialnerves Eyes: Droopingeyelids (ptosis), inabilitytomoveeyes (externalophthalmoplegia), blindness (retinitispigmentosa, opticatrophy), cataracts Sceletalmuscle: Muscleweakness, exerciseintolerance, cramps, excretion of muscle protein myoglobininurine (myoglobulinuria) Heart: Cardiomyopathy (cardiacmuscleweakness), conductionblock Pancreas: Diabetes Liver: Liverfailure (uncommonexceptinbabieswithmtDNAdepletionsyndrome), fattyliver (hepaticsteatosis) Kidneys: Falconi’ssyndrome (loss of essentialmetabolitesinurine), nephroticsyndrome (uncommonexceptforinfantswithcoenzyme Q10 deficiency) Digestivetract: Difficultswallowing, vomiting, feeling of being full, chronicdiarrhea, symptoms of intestinalobstruction

  10. Mitochondrialdiseasesclassified

  11. Diseases of mtDNAorigin • Same polymorphisms are related to complex diseases and longevity • No symptomuntilmtDNAmutation ratio > 60% • Clonalexpansion of mutantmtDNAmayoccur • Cytochrome c oxidase (COX) defectas marker

  12. ROS and their major sources • Theory of Denham Harman in 1972 • Molecule with unpaired electron • Mitochondrial respiratory chain leakage (90%) • Dopamine, nor-epinephrine • NOS (nitric oxide synthase) • Respiratory bursts of leukocytes • Environmental stimuli causing redox disbalance

  13. Antioxidants • SOD (CuZnSOD, MnSOD, FeSOD) • Catalase • Glutathioneperoxidase • Vitamins C, E • Carotenoids • Coenzyme Q10 • Glutathione (GSH) • Uricacide

  14. Mitochondrial oxygen radical theory of aging (fulfilment of major aging theory criteria) • ROS production is endogenous • Continuouseffect, changesprogressivewithage • DeleteriouseffectsonmtDNA • Irreversibleeffects

  15. Mitochondrial ROS runaway Nuclear DNA encodedsubunits Mitochondria ATP Oxidative phosporylation system NADH, FADH2 O2 mtDNAencoded subunits Electron leak Defectiveelectron transportchain SOD mtDNA H2O O2∙ H2O2 2 GSH Fenton reaction DefectivemtDNA encodedsubunits Viciouscycle GPX CAT ∙OH GSSG Strand breakage basemodification H2O + ½ O2 + 2 H2O Lipidperoxidation Protein oxidation mtDNA mutations Innermembrane Outermembrane Aging and mitochondrialdisease Energy deficit

  16. Mitochondrial ROS production • Mitochondrial ROS production is relevant parameter of aging • Anti-oxidants are usually not rate-limiting • Issues of CuZnSOD /MnSOD / FeSOD, GSH-peroxidase • Complex I of respiratory chain is main target and source of aging rate • Caloric restriction targets complex I as well

  17. mtDNAoxidativedamage • Marker for oxidative mtDNA damage: 8-oxodG • 8-oxodG level is 10x > in mtDNA than in gDNA • Inefficientrepair of 8-oxodG mtDNAdamage • 8-oxodG alone is alsomutagenic • Calorierestrictiontargets 8-oxodG levelsaswell

  18. Mitochondrialapoptosisdueto ex. stimulus STRESS/STARVATION Fas NMDA/AMPA ASIC Ca2+ Caspase-8 ROS Calpains Bax Bax Bid Bcl-xL Bax P Bcl-2 tBid p53 Bax Bax Bax Mitochondria P tBid Bax p53 Nucleophosmin Cytc DNA damage AIF Nucleus APOPTOSIS Cytc Caspase-3 Caspase-9 Apaf-1

  19. Lipidperoxidation • PUFA residues are sensitive to ROS • PUFA areboth ROS targets and mediators • PUFA content of mtmembraneaffectslife-span

  20. PUFA controversy: AA and DHA • HOMEOVISCOUS LONGEVITY ADAPTATION • DBI negativelycorrelateswithsize and MLS • Detrimentalin vivo (mt, heart, neuralsystem etc.) • SAM-P strainwithincreased AA and DHA levels • MDA-lysineadductsasmarkersfor protein oxidativestresslevel

  21. Protein peroxidation • MDA-lysineadductsasmarkersfor protein oxidativestresslevel • Oxidation of protein backbone • Formation of protein cross-linkages • Oxidation of aminoacidsidechains • Protein fragmentation

  22. Repairfollowing protein peroxidation • Direct: re-reduction of oxidizedsulfhydrilgroups • Indirect: • Recognition, removal, degradation (proteasome, calpain, lysosome) • Replacement, re-utilization • Storage aslipofuscin (age pigment, ceroid)

  23. Protein peroxidation and diseases • Increasedlevels of oxidizedproteinsAlzheimer’sdisease, ALS, cataract, RA, musculardystrophy, RDS, progeria, Parkinson’sdisease, Werner syndrome • Elevatedcontent of modifiedproteinsCardiovascular, Alzheimer’sdisease, atherosclerosis, Parkinson’sdisease • Increasedlevels of protein glycation / glycoxidationDM, atherosclerosis, Alzheimer’sdisease, Parkinson’sdisease • Elevatedcontent of protein nitrotyrosinedamageAlzheimer’sdisease, SM, lunginjury, atherosclerosis

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