Control of Mitochondrial Integrity of Aging

Yıl 2018, Cilt: 4 Sayı: 1, 680 - 705, 15.04.2018

Yusuf Döğüş , Mehmet Akif Çürük

https://doi.org/10.30569/adiyamansaglik.396221

Öz

Aging is a natural cause of
progressive decline in tissue and organ functions, leading to an increased risk
of disease and death. Among the various factors contributing to human aging,
mitochondrial dysfunction is emerging as one of the most important factors.
Mitochondrial dysfunction is linked to the development of age-related
pathologies such as metabolic syndrome, neurodegenerative disorders, cardiovascular
diseases and cancer. Mitochondria are central to the regulation of energy and
metabolic homeostasis and have a complex system to limit mitochondrial damage
and provide mitochondrial integrity and function. Several
molecular and cellular pathways in eukaryotes are involved in controlling the
quality and integrity of mitochondria. These pathways are
concerned with the functioning of the organism in a healthy manner throughout
its life cycle. The regulation of the integrity of
mitochondrial DNA (mtDNA) as well as the mitochondrial complexes that determine
mitochondrial functions and the regulation of expression are necessary for the
reshaping of single proteins. Mitochondria; Understanding of the underlying
mechanisms in genomic, proteomic, organellar and cellular levels is the basis
for intervening in age-related diseases resulting from mitochondrial
dysfunctions, degenerative processes, aging and deterioration of mitochondria.
Quality
control (QC) systems prevent processes such as degenerative diseases and aging
that cause organ dysfunction. The subject of this review; the
mitochondrial regulation which causes the elucidation of the aging process,
which is still not fully understood today. Pathways to disease and
aging in mitochondrial QC; mtDNA repair and reorganization, regeneration of
oxyde aminoacids, refolding and disruption of heavily damaged proteins,
degradation of mitochondria entirely by mitofargin, and eventually programmed
cell death.

Anahtar Kelimeler

Aging, Mitochondria, Aging Control

Yaşlanmanın Mitokondriyal Bütünlüğünün Denetlenmesi

Öz

Yaşlanma, doku ve organ
fonksiyonlarında ilerleyici gerileme ile karakterize, hastalık ve ölüm riskinde
artışa neden olan doğal bir olaydır. İnsan yaşlanmasına katkıda bulunan çeşitli
faktörler arasında, mitokondrial disfonksiyon en önemli etkenlerden biri olarak
ortaya çıkmaktadır. Mitokondrial disfonksiyon metabolik sendrom,
nörodejeneratif bozukluklar, kardiyovasküler hastalıklar ve kanser gibi yaşla
ilişkili patolojilerin gelişimi ile bağlantılıdır. Mitokondri, enerji ve
metabolik homeostazın düzenlenmesinde merkezi olup mitokondrial hasarı
sınırlandıran ve mitokondrial bütünlüğü ve işlevi sağlamak için karmaşık bir
sisteme sahiptir. Ökaryotlarda çeşitli moleküler ve hücresel yolaklar,
mitokondrinin kalitesini ve bütünlüğünü kontrol etmek için etkindir. Bu
yolaklar, organizmanın ömrü boyunca bu temel organelin sağlıklı bir şekilde işlevini
gerçekleştirmesi ile ilgilidir. Mitokondrial fonksiyonları belirleyen mitokondrial
komplekslerin yanısıra mitokontriyal DNA (mtDNA)'nın bütünlüğünün denetlenmesi
ve ekspresyonunun düzenlenmesi, tekli proteinlerin yeniden şekillendirilmesi
için gereklidir. Mitokondri; genomik, proteomik, organeller ve hücresel
seviyelerdeki altta yatan mekanizmaların anlaşılması, mitokondrial fonksiyon
bozuklukları, dejeneratif süreçler, yaşlanma ve mitokondriyanın bozulmasından
kaynaklanan yaşa bağlı hastalıklar için müdahale etmenin temelidir. Kalite
kontrol (Quality control: QC) sistemleri, organellerin işlev bozukluğuna yol
açan dejeneratif hastalıklar ve yaşlanma gibi süreçleri engeller. Bu derlemenin
konusu; bugün hala tam olarak açıklanamayan yaşlanma sürecinin aydınlatılmasına
neden olan mitokandriyal düzenlemenin incelenmesidir. Mitokondrial QC'de
hastalık ve yaşlanma ile ilgili yolaklar; mtDNA onarımı ve yeniden
organizasyonu, okside aminoasit rejenerasyonu, ağır hasar gören proteinlerin
yeniden katlanması ve parçalanması, mitofajinin tümüyle mitokondrinin bozulması
ve sonunda programlanmış hücre ölümü tartışılacaktır.

Anahtar Kelimeler

Yaşlanma, Mitokondri, Yaşlanmanın Kontrolü

Kaynakça

• 1. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow G.J, Morimoto RI, Pessin JE, et al. Geroscience. Linking aging to chronic disease. Cell. 2014;159:709–713.
• 2. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–1217.
• 3. Kirkwood TBL. Understanding the odd science of aging. Cell. 2005;120:437–447.
• 4. Kirkwood TBL. A systematic look at an old problem. Nature. 2008;451:644–647.
• 5. Lopez-Otin C, Galluzzi L, Freije JMP, Madeo F, Kroemer G. Metabolic control of longevity. Cell. 2016;166:802–821.
• 6. Harman D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 1956;11:298–300.
• 7. Nicholls DG. Mitochondria and calcium signaling. Cell Calcium. 2005;38:311–317.
• 8. Srivastava S. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clin. Transl. Med. 2016;1:5-25.
• 9. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol. Cell. 2016;61:654–666.
• 10. Kauppila TES, Kauppila JHK, Larsson NG. Mammalian mitochondria and aging: An update. Cell Metab. 2017;25:57–71.
• 11. Palikaras K, Lionaki E, Tavernarakis N. Coupling mitogenesis and mitophagy for longevity. Autophagy 2015;11:1428–1430.
• 12. Meisinger C, Sickmann A, Pfanner N. The mitochondrial proteome: from inventory to function. Cell. 2008;134:22–24.
• 13. Pagliarini DJ, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134:112–123.
• 14. Koopman WJ, Distelmaier F, Smeitink JA, Willems PH. OXPHOS mutations and neurodegeneration. EMBO J. 2013;32:9–29.
• 15. Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial disorders. N. Engl. J. Med. 2012;366:1132–1141.
• 16. Piko L, Hougham AJ, Bulpitt KJ. Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: evidence for an increased frequency of deletions/additions with aging. Mech. Ageing Dev. 1988;43:279–293.
• 17. Rizet G. Impossibility of obtaining uninterrupted and unlimited multiplication of the ascomycete Podospora anserina. C.R. Hebd. Seances Acad. Sci. 1953;237:838–840.
• 18. Belcour L. Mitochondrial DNA and senescence in Podospora anserina. Curr. Genet. 1981;4:81–82.
• 19. Kuck U, Stahl U, Esser K. Plasmid-like DNA is part of mitochondrial DNA in Podospora anserina. Curr. Genet. 1981;3:151–156.
• 20. Osiewacz HD, Esser K. The mitochondrial plasmid of Podospora anserina: a mobile intron of a mitochondrial gene. Curr. Genet. 1984;8:299–305.
• 21. Stahl U, Lemke PA, Tudzynski P, Kuck U, Esser K. Evidence for plasmid like DNA in a filamentous fungus, the ascomycete Podospora anserina. Mol. Gen. Genet. 1978;162:341–343.
• 22. Cummings DJ, Belcour L, Grandchamp C. Mitochondrial DNA from Podospora anserina. II. Properties of mutant DNA and multimeric circular DNA from senescent cultures. Mol. Gen. Genet. 1979;171:239–250.
• 23. Kuck U, Esser K. Genetic map of mitochondrial DNA in Podospora anserina. Curr. Genet. 1982;5:143–147.
• 24. Griffiths AJ. Fungal senescence. Annu. Rev. Genet. 1992;26:351–372.
• 25. Osiewacz HD. Molecular analysis of aging processes in fungi. Mutat. Res. 1990;237:1–8.
• 26. Piko L, Bulpitt KJ, Meyer R. Structural and replicative forms of mitochondrial DNA in tissues from adult and senescent BALB/c mice and Fischer 344 rats. Mech. Ageing Dev. 1984;26:113–131.
• 27. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989;1:642–645.
• 28. Melov S, Hertz GZ, Stormo GD, Johnson TE. Detection of deletions in the mitochondrial genome of Caenorhabditis elegans. Nucleic Acids Res. 1994;22:1075–1078.
• 29. Kadenbach B, Muller-Hocker J. Mutations of mitochondrial DNA and human death. Naturwissenschaften. 1990;77:221–225.
• 30. Boursot P, Yonekawa H, Bonhomme F. Heteroplasmy in mice with deletion of a large coding region of mitochondrial DNA. Mol. Biol. Evol. 1987;4:46–55.
• 31. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988;331:717–719.
• 32. Wallace DC. Mitochondrial DNA mutations and neuromuscular disease. Trends Genet. 1989;5:9–13.
• 33. Sciacco M, Bonilla E, Schon EA, DiMauro S, Moraes CT. Distribution of wild-type and common deletion forms of mtDNA in normal and respirationdeficient muscle fibers from patients with mitochondrial myopathy. Hum. Mol. Genet. 1994;3:13–19.
• 34. Mancuso M et al. Phenotypic heterogeneity of the 8344A.G mtDNA ‘MERRF’ mutation. Neurology. 2013;80:2049–2054.
• 35. Chinnery PF, Hudson G, Mitochondrial genetics. Br Med Bull. 2013;106:135-159
• 36. Rossignol R, Malgat M, Mazat JP, Letellier T. Threshold effect and tissue specificity. Implication for mitochondrial cytopathies. J. Biol. Chem. 1999;274:33 426–33 432.
• 37. Blackwood JK, Whittaker RG, Blakely EL, Alston CL, Turnbull DM, Taylor RW. The investigation and diagnosis of pathogenic mitochondrial DNA mutations in human urothelial cells. Biochem. Biophys. Res. Commun. 2010;393:740–745.
• 38. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat. Rev. Genet. 2005;6:389–402.
• 39. McFarland R, Turnbull DM. Batteries not included: diagnosis and management of mitochondrial disease. J. Intern. Med. 2009:265:210–228.
• 40. Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, McBride HM, Park DS, Fon EA. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 2012;13:378–385.