Genome-Wide Analysis of Mitochondrial DNA (mtDNA)-Nuclear DNA Interaction in Age-Related Macular Degeneration (AMD)
Patrice J. PersadMonique D. CourtenayGaofeng WangWilliam H. CadeAnita AgarwalStephen G. SchwartzJaclyn L. KovachJonathan L. HainesMargaret A. Pericak‐VanceWilliam K. Scott
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Nuclear DNA
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Mitochondria not only provide necessary energy for cells, but more importantly, they participate in the regulation of various biological functions and activities of cells. As one of the critical components of the body’s genome, mitochondrial genome (mtDNA) is the key to cell bioenergetics and genetics. However, since no protection of histones and a complete self-repair system, mtDNA is extremely prone to mutate. Human diseases caused by mtDNA mutations are only transmitted through the maternal line. The same phenotype can come from multiple mtDNA mutations, and the same mtDNA mutation can lead to multiple phenotypes. This is the major reason that makes the diagnosis and identification of mtDNA genetic diseases difficult. Meanwhile, mtDNA mutations may be the culprit involved in mediating the aging and tumorigenesis. Currently, no effective therapeutics for diseases caused by mtDNA mutations, but with the deepening of research and technological advancement, it is promising that breakthroughs in the diagnosis and treatment of mitochondrial-related diseases in the near future.
Heteroplasmy
Human mitochondrial genetics
Mitochondrial disease
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Human mitochondrial genetics
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Background Mitochondria play an important role in cell survival, function and lineage differentiation. Changes in mitochondrial DNA (mtDNA) may control mitochondrial functions and thus may impart an alternative cellular state thereby leading to a disease condition in the body. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease wherein immune cells become self-reactive causing joint inflammation, swelling and pain in patients. The changes in mtDNA may alter cellular functions thereby directing the immune cells towards an inflammatory phenotype in RA. Therefore, it becomes pertinent to identify changes in mtDNA sequence in immune cells of RA patients to understand the pathogenesis and progression of RA.Methods mtDNA from peripheral blood mono-nuclear cells (PBMCs) of 23 RA patients and 17 healthy controls (HCs) were sequenced using next-generation sequencing (NGS). Further, single nucleotide polymorphisms (SNPs) and other variable changes in mtDNA hypervariable and coding regions, amino acid changes with a putative impact on disease, levels of heteroplasmy, copy number variations and haplogroup analysis in RA patients and HCs were analysed and compared to identify any association of mtDNA changes and RA disease.Results A total of 382 single nucleotide mtDNA variants were observed, 91 (23.82%) were present in hypervariable region and 291 (76.18%) in coding region of patients and HC. The variant 513 GCA > ACA, with G present in HVR-III, known to control the mitochondrial translation function, was significantly present in RA patients. The CYTB gene had larger number of SNPs in HC samples while RNR2 was more variable in RA patients. A non-synonymous heteroplasmy in ND1 gene was found at a single nucleotide position 3533 in an increased number of RA patients as compared to the controls. A significant increase in mtDNA duplication and a higher frequency of the haplogroup U was also characteristic of RA. Also, the presence of SNPs in mitochondrial tRNA genes at two positions 12308 A > G and 15924 A > G were found to be pathogenic.Conclusion We herein observed an altered mtDNA sequence in immune cells of RA patients and thus a possible role of mitochondrial genome in the development of RA. The observed nucleotide changes in mtDNA control region, RNR2 gene, increased heteroplasmy and mtDNA duplication in RA patients may alter sites for transcription factor binding thereby influencing mtDNA gene expression, as well as copy numbers thereby affecting the mitochondrial proteins and their functions. These changes in mtDNA could be one of the probable reasons among many leading to the progression of RA.
Heteroplasmy
Hypervariable region
Pathogenesis
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Human mitochondrial genetics
Heteroplasmy
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ミトコンドリア病の多くの症例から特定の点突然変異や欠失突然変異を有したミトコンドリアDNA（mtDNA）が検出されている．さらに，糖尿病や神経変性疾患の発症や個体老化にも変異型mtDNAの関与が示唆されており，ミトコンドリアゲノム変異と多様な病態との因果関係が注目を集めている．このような状況の中，われわれは世界に先駈けて病原性欠失突然変異型mtDNA（欠失型mtDNA）を導入したマウス（ミトマウス）の作製に成功した．欠失型mtDNAを80%以上含有するミトマウスはミトコンドリア病でみられるような多様な病態を発症することから，ミトマウスはミトコンドリア病のモデルマウスであると結論できた．ミトマウスの登場によって，ミトコンドリア病の病態発症機構の解明だけでなく，効果的な治療法を探索するための環境がようやく整ったといえる．
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Abnormal mitochondria have long been hypothesized to be involved in tumorigenesis. Mitochondrial DNA (mtDNA) mutations have been found in various cancer cells, yet their role in tumorigenesis remains largely unknown. Our long-term goal is to understand the role of mtDNA polymorphism and mtDNA mutations in tumorigenesis. We focused on the role of the mtDNA haplogroup; a 4,977 bp common mtDNA deletion; mtDNA mutations in the main control region of mtDNA or displacement loop; and mtDNA heteroplasmy in cancer occurrence and cancer development. Our results indicate that qualitative and quantitative changes in mtDNA play an important role in cancer development.
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Haplogroup
mtDNA control region
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Mitochondrial DNA(mtDNA) determines the primary nature of mitochondrial and plays an important role in cell function.The damage of mtDNA is associated with aging, tumor and other diseases. DNA methylation is a major way to regulate gene expression. mtDNA expression is regulated by nuclear DNA. mtDNA and nDNA participating in metabolic regulation and pathogenesy synergisticly. The relationship between mitochondrial DNA and DNA methylation were reviewed here.
Nuclear DNA
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