Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes

Liu, Chunyu; Fetterman, Jessica L.; Liu, Poching; Luo, Yan; Larson, Martin G.; Vasan, Ramachandran S.; Zhu, Jun; Levy, Daniel

doi:10.1007/s00439-018-1873-4

Cited by 21 publications

(20 citation statements)

References 46 publications

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“…2) 7,20,21 . As previously reported 22,23 , mutational spectrum indicated a high transition to transversion (Ti/Tv) ratio of 16.44 ( Supplementary Fig. 3).…”

Section: Resultssupporting

confidence: 83%

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

et al. 2020

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The genetic landscape of mitochondrial DNA (mtDNA) has been elusive. By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Frequency spectra of the haplogroups were population-specific and were heterogeneous among geographic regions within Japan. Application of machine learning methods could finely classify the subjects corresponding to the high-digit mtDNA sub-haplogroups. mtDNA had distinct genetic structures from that of nuclear DNA (nDNA), characterized by no distance-dependent linkage disequilibrium decay, sparse tagging of common variants, and the existence of common haplotypes spanning the entire mtDNA. We did not detect any evidence of mtDNA-nDNA (or mtDNA copy number-nDNA) genotype associations. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. We observed pleiotropy of mtDNA genetic risk on the five late-onset human complex traits including creatine kinase (P = 1.7 × 10 −12).

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“…2) 7,20,21 . As previously reported 22,23 , mutational spectrum indicated a high transition to transversion (Ti/Tv) ratio of 16.44 ( Supplementary Fig. 3).…”

Section: Resultssupporting

confidence: 83%

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

et al. 2020

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“…This finding was unexpected, as previous studies have identified increasing MtHz with age. Sequencing of blood DNA from 356 individuals from the Framingham Heart Study found elevated MtHz at multiple positions across the genome with increasing age ( 34 ). Similarly, a study of 2077 Sardinians using leukocyte DNA also found increasing MtHz and copy number reduction with increasing age ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Nuclear genome-wide associations with mitochondrial heteroplasmy

et al. 2021

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The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of heteroplasmy itself is deleterious. However, mitochondrial heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of heteroplasmy. GWAS identified 20 loci for heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (TFAM), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial heteroplasmy has a heritable nuclear component.

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“…NDUFV1, NDUFS1, NDUFA13, NDUFC2, and NDUFB5 are NADH-dehydrogenases of mitochondria (25). NADH-dehydrogenase is one of the most important enzyme of complex I (26). Results of KEGG pathway analysis reveal that these differentially proteins are involved in ribosome, ECM-receptor interaction, oxidative phosphorylation, pyruvate metabolism, glucagon signaling pathway, and fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

microRNA-222 Attenuates Mitochondrial Dysfunction During Transmissible Gastroenteritis Virus Infection

Zhao

Song

Bai

et al. 2019

Molecular & Cellular Proteomics

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In BriefZhao et al. identify microRNA-222 as a mediator of mitochondrial dysfunction, THBS1, and CD47 induced during TGEV infection and showed that mi-croRNA-222 inhibits TGEV-induced mitochondrial dysfunction via targeting and downregulating CD47. Graphical Abstract Highlights• microRNA-222 attenuates TGEV-induced mitochondrial dysfunction.• microRNA-222 downregulates THBS1 and CD47.• THBS1 is the target of microRNA-222 during TGEV infection.• THBS1 and CD47 increase mitochondrial Ca 2ϩ level and reduced mitochondrial membrane potential (MMP). Transmissible gastroenteritis virus (TGEV) is a member of Coronaviridae family. Our previous research showed that TGEV infection could induce mitochondrial dysfunction and upregulate miR-222 level. Therefore, we presumed that miR-222 might be implicated in regulating mitochondrial dysfunction induced by TGEV infection. To verify the hypothesis, the effect of miR-222 on mitochondrial dysfunction was tested and we showed that miR-222 attenuated TGEV-induced mitochondrial dysfunction. To investigate the underlying molecular mechanism of miR-222 in TGEV-induced mitochondrial dysfunction, a quantitative proteomic analysis of PK-15 cells that were transfected with miR-222 mimics and infected with TGEV was per-formed. In total, 4151 proteins were quantified and 100 differentially expressed proteins were obtained (57 upregulated, 43 downregulated), among which thrombospondin-1 (THBS1) and cluster of differentiation 47 (CD47) were downregulated. THBS1 was identified as the target of miR-222. Knockdown of THBS1 and CD47 decreased mitochondrial Ca 2؉ level and increased mitochondrial membrane potential (MMP) level. Reversely, overexpression of THBS1 and CD47 elevated mitochondrial Ca 2؉ level and reduced mitochondrial membrane potential (MMP) level. Together, our data establish a significant role of miR-222 in regulating mitochondrial dysfunction in response to TGEV infection.

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Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes

Cited by 21 publications

References 46 publications

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population

Nuclear genome-wide associations with mitochondrial heteroplasmy

microRNA-222 Attenuates Mitochondrial Dysfunction During Transmissible Gastroenteritis Virus Infection

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