The base excision repair pathway is initiated by the action of a class of enzymes known as DNA glycosylases, which recognize and release the damaged base, and thus give specificity to the repair process. Mammalian cells carry two major DNA glycosylases for the repair of oxidized bases, oxoguanine DNA glycosylase (OGG1) and Endonuclease III homologue (NTH1). We found that OGG1 plays a crucial role in the repair of oxidized lesions in mitochondria and is probably the only DNA glycosylase for 8-oxoG removal in these organelles. All BER enzymes are encoded in the nucleus and transported to mitochondria;however there is very limited information on the regulation of mitochondrial BER. In mammalian mitochondria the mtDNA is found in a large protein-DNA complex known as the nucleoid. One of the most abundant protein components of mammalian nucleoids is the transcription factor TFAM, which has been postulated to have a structural function in compacting mtDNA into the nucleoid structure. Previously, we found that TFAM could inhibit BER proteins and mitochondrial pol gamma. We proposed that TFAM may be functioning like nuclear histones and therefore proposed that a TFAM remodeling protein must exit in mitochondria to allow for mtDNA metabolism. In separate studies, we documented that RECQL4 and CSB were present in mitochondria, thus we evaluated if each protein could relieve TFAM inhibition. We observed CSB, but not RECQL4, could display TFAM and alleviate its inhibition. We are continuing to search for and interrogate protein-interaction with TFAM in an attempt to more fully characterize mtDNA repair and metabolism

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000733-18
Application #
8736603
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2013
Total Cost
$536,929
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Fang, Evandro Fei; Scheibye-Knudsen, Morten; Chua, Katrin F et al. (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308-21
Cheng, Aiwu; Yang, Ying; Zhou, Ye et al. (2016) Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges. Cell Metab 23:128-42
Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten et al. (2016) Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab 23:1093-112
Hou, Yujun; Song, Hyundong; Croteau, Deborah L et al. (2016) Genome instability in Alzheimer disease. Mech Ageing Dev :
Hey-Mogensen, Martin; Gram, Martin; Jensen, Martin Borch et al. (2015) A novel method for determining human ex vivo submaximal skeletal muscle mitochondrial function. J Physiol 593:3991-4010
Bürkle, Alexander; Grune, Tilman; Gonos, Efstathios S et al. (2015) Editorial. Mech Ageing Dev 151:1
Soerensen, Mette; Nygaard, Marianne; Dato, Serena et al. (2015) Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals. Aging Cell 14:60-6
Fang, Evandro Fei; Scheibye-Knudsen, Morten; Jahn, Heiko J et al. (2015) A research agenda for aging in China in the 21st century. Ageing Res Rev 24:197-205
Scheibye-Knudsen, Morten; Fang, Evandro F; Croteau, Deborah L et al. (2015) Protecting the mitochondrial powerhouse. Trends Cell Biol 25:158-70
Maynard, S; Keijzers, G; Hansen, A-M et al. (2015) Associations of subjective vitality with DNA damage, cardiovascular risk factors and physical performance. Acta Physiol (Oxf) 213:156-70

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