Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA

Rusecka, Joanna; Kaliszewska, Magdalena; Bartnik, Ewa; Tońska, Katarzyna

doi:10.1007/s13353-017-0424-3

Cited by 75 publications

(61 citation statements)

References 92 publications

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“…As mtCN of individuals is known to be correlated with mitochondrial functions regulated by the nDNA genes 3,4 , we also investigated the mtCN-nDNA genotype association. Each mtCN of the individual was estimated by the WGS depth.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…Hundreds of mitochondria reside in a single cell and each mitochondrion has several mtDNA molecules in itself. Furthermore, 1000-2000 mitochondria-related genes in nuclear DNA (nDNA) have been identified, which regulate gene expressions and mtDNA copy numbers (mtCNs) via interactions with mtDNA [3][4][5][6] .…”

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confidence: 99%

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

et al. 2020

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“…A priori, we expect that mitochondrially encoded gene expression would be positively correlated with mtDNA-CN. Likewise, multiple nuclear encoded genes are involved in the regulation of mtDNA replication, and thus, expression levels of these genes are expected to be correlated with mtDNA-CN [23,24]. We therefore evaluated the associations between mtDNA-CN and expression of these two classes of genes, correcting for cohort, sample ischemic time, genotyping PCs, age, race, and surrogate variables derived from RNA-sequencing data to capture known and hidden confounders (Supp.…”

Section: Association Of Mtdna-cn Derived From Whole Blood With Gene Ementioning

confidence: 99%

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Yang

Castellani

Longchamps

et al. 2020

Preprint

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Mitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues. We evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35). In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90). The observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.

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“…Among mitochondrial transcription machinery constituents, only TFAM mutations are well established to contribute to human disease [17]. TFAM binds DNA in both sequence-specific and nonspecific manners.…”

Section: Mitochondrial Transcriptionmentioning

confidence: 99%

Mitochondrial Gene Expression and Beyond—Novel Aspects of Cellular Physiology

Kotrys

Szczęsny

2019

Cells

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Mitochondria are peculiar organelles whose proper function depends on the crosstalk between two genomes, mitochondrial and nuclear. The human mitochondrial genome (mtDNA) encodes only 13 proteins; nevertheless, its proper expression is essential for cellular homeostasis, as mtDNA-encoded proteins are constituents of mitochondrial respiratory complexes. In addition, mtDNA expression results in the production of RNA molecules, which influence cell physiology once released from the mitochondria into the cytoplasm. As a result, dysfunctions of mtDNA expression may lead to pathologies in humans. Here, we review the mechanisms of mitochondrial gene expression with a focus on recent findings in the field. We summarize the complex turnover of mitochondrial transcripts and present an increasing body of evidence indicating new functions of mitochondrial transcripts. We discuss mitochondrial gene regulation in different cellular contexts, focusing on stress conditions. Finally, we highlight the importance of emerging aspects of mitochondrial gene regulation in human health and disease.

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Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA

Cited by 75 publications

References 92 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

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Mitochondrial Gene Expression and Beyond—Novel Aspects of Cellular Physiology

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