Aurora Gómez-Durán

Centro de Investigaciones Biologicas "Margarita Salas" · CSIC

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in...

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA (mtDNA) mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of s...

Vascular smooth muscle cell (VSMC) proliferation is essential for arteriogenesis to restore blood flow after artery occlusion, but the mechanisms underlying this response remain unclear. Based on our previous findings showing increased VSMC proliferation in the neonatal aorta of mice lacking the protease MT4-MMP, we aimed at discovering new players...

Methylation on CpG residues is one of the most important epigenetic modifications of nuclear DNA, regulating gene expression. Methylation of mitochondrial DNA (mtDNA) has been studied using whole genome bisulfite sequencing (WGBS), but recent evidence has uncovered technical issues which introduce a potential bias during methylation quantification....

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N...

Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored, partly due to a lack of genotype calling and quality-control procedures. Developing an at-scale workflow for mtDNA variant analyses, we show correlations between nuclear and mitochondrial genomic structures within subpopulations of Great Britain and establish a UK Bioban...

Most humans carry a mixed population of mitochondrial DNA (mtDNA heteroplasmy) affecting ~1–2% of molecules, but rapid percentage shifts occur over one generation leading to severe mitochondrial diseases. A decrease in the amount of mtDNA within the developing female germ line appears to play a role, but other sub-cellular mechanisms have been impl...

Methylation on CpG residues is one of the most important epigenetic modifications of nuclear DNA, regulating gene expression. Methylation of mitochondrial DNA (mtDNA) has been studied using whole genome bisulfite sequencing (WGBS), but recent evidence has uncovered major technical issues which introduce a potential bias during methylation quantific...

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6‐months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected...

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected...

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6 months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation, however only ∼1/100 carriers develop the disease. We studied 27 affected an...

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutati...

Detection of human mitochondrial DNA variants and quantification of heteroplasmy have quickly evolved since the discovery of the mitochondrial genome in the early 1960s. Traditionally, mitochondrial variants were studied through a combination of molecular biology techniques, often limited to the analysis of single variants. The development of Sange...

Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In Drosophila, knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we de...

mtDNA is transmitted through the maternal line and its sequence variability, which is population specific, is assumed to be phenotypically neutral. However, several studies have shown associations between the variants defining some genetic backgrounds and the susceptibility to several pathogenic phenotypes, including neurodegenerative diseases. Man...

In order to limit the adverse effects of excessive inflammation, anti-inflammatory responses are stimulated at an early stage of an infection, but during sepsis these can lead to deactivation of immune cells including monocytes. In addition, there is emerging evidence that the up-regulation of mitochondrial quality control mechanisms, including mit...

[This corrects the article DOI: 10.1371/journal.pgen.1007126.].

The m.1555A>G mitochondrial DNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmi...

Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples...

Correlation of allele frequency (AFs) of the variants between 17,815 sub-haplogroup tagged mtDNA sequences and 12,691 non sub-haplogroup tagged sequences in NCBI database. (a) The allele frequencies of variants in 12,691 non sub-haplogroup tagged sequences were highly correlated with 17,815 sub-haplogroup tagged sequences within each marco-haplogro...

Correlation of allele frequency (AFs) of the variants between 1000 Genome Project and 30,506 NCBI mtDNA sequences, AFs were shown in log2(AF/1-AF). The allele frequencies of variants in 1000 Genome Project were highly correlated with 30,506 NCBI mtDNA sequences within each marco-haplogroup. L, M and N groups were shown, respectively. (EPS)

Comparison of the presence of specific disease causing mtDNA mutations in each macro-haplogroup. Columns left to right: mtDNA variant; mutations specific to macro-haplogroup L (blue); mutations specific to macro-haplogroup M (pink); mutations specific to macro-haplogroup N (green); mutations found on all three macro-haplogroups L,M&N (purple); muta...

Comparison of the distribution of CpG% (%C>T) in macro-haplogroups. (a) Distribution of CpG% (%C>T) in all possible variants. (b) distribution of CpG% (%C>T) in disease-causing mutations. (EPS)

Correlation of allele frequencies (AFs) of non haplogroup makers between 1000 Genome Project and 30,506 NCBI mtDNA sequences, AFs were shown in log2(AF/1-AF). Macro-haplogroup L, M and N were shown in different colors, respectively. (EPS)

Correlation of pathogenicity score between polymorphisms and disease-causing mutations. (a) The correlation of mean pathogenicity score between all variants of each mtDNA sequence and only disease-causing mutations of each mtDNA sequence. (b) The correlation of mean pathogenicity score between non-disease-causing mutations of each mtDNA sequence an...

Sample size of each haplogroup and macro-haplogroup. (DOCX)

The details of 202 reported pathogenic variations in ClinVar. (XLSX)

The details of 57 defined disease-causing mutations in 30,506 mtDNA sequences. (XLSX)

The categories of mutational signatures observed in 30,506 mtDNA sequences. 30,506 mtDNA sequences were realigned against Reconstructed Sapiens Reference Sequence (RSRS). The probability bars for the six types of substitutions (C>A, C>G, C>T, T>A, T>C and T>G) are displayed within each macro-haplogroup. (EPS)

Comparison of the CpG% between all possible variants and disease-causing mutations for the entire population and each group. The percentage of variants in CpG region and the p-value for Fisher’s exact test—all possible variants vs all disease-causing mutations in the entire population and each group were shown and calculated. (DOCX)

The Pathogenicity scores of all possible protein variants. (XLSX)

The mtDNA sequences IDs and haplogroup of each sequence used in this study. 17,815 of the 30,506 mtDNA sequences which was possible to identify all known appropriate haplogroup markers down to the sub-haplogroup level were labeled as sub-haplogroup tagged in the QC column. (XLSX)

Comparison of the CpG% between any two of three groups. The p-value for Fisher’s exact test—each group vs the rest of groups were shown and calculated. (DOCX)

The m.1555A4G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555...

Monocytes from sepsis patients have mitochondrial DNA (mtDNA) depletion and immune deactivation. Here we find that THP-1 cell immune responses are impaired by experimentally depleting mtDNA, through dysregulated immune signalling, and rescued by interferon-γ treatment.

Monocytes from sepsis patients have mitochondrial DNA (mtDNA) depletion and immune deactivation. Here we find that THP-1 cell immune responses are impaired by experimentally depleting mtDNA, through dysregulated immune signalling, and rescued by interferon-γ treatment.

Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA cod...

mtDNA variants in pedigree I. Base indicates the position relative to the revised Cambridge reference sequence of human mitochondrial DNA; the GB frequency data is derived from 29,867 GenBank sequences with size greater than 15.4kbp and published on the MITOMAP database. A value of 1 indicates 100% prevalence.[7] The mitochondrial haplotype is N1a1...

Increased mtDNA copy number in patient fibroblasts. Mitochondrial copy number was assessed by quantitative RT-PCR for the mitochondrial gene ND1 and the nuclear gene B2M and normalized to the mean ratio of healthy controls. As a group, patient-derived fibroblasts showed a significant increase in copy number relative to control fibroblasts (of diffe...

Fully annotated mitoSILAC data. Individual subunits of the respiratory complexes identified in at least two of the four mitoSILAC experiments are listed. The binary logarithm of the fold change is shown (LogFC). Error bars are shown where the standard deviation exceeded 20% of the mean. The adjusted p value indicating significant changes is indicat...

Linkage analysis demonstrates lack of autosomal inheritance. (A) Linkage analysis was performed on all affected individuals (n = 16) with elevated creatinine, using SNP data from the Illumina CytoSNP 12 chip (Illumina, USA). Rare dominant and X-linked models were used and the maximal LOD score (2.64) was considered non-significant given the size of...

m.547A>T cybrids display reduced protein translation. Mitochondrial protein translation was analysed by blocking cytosolic translation with emetine in the presence of 35S methionine and cysteine. (A) A clear reduction of mitochondrial protein synthesis was observed in the patient-derived cybrids with the m.547A>T substitution. The characteristic ba...

Citrate synthase activity of patient and control fibroblasts. Citrate synthase activity in total cell lysates was assessed by measuring the conversion of oxaloacetate and acetyl CoA to citrate and CoA-SH, which then reacts with dithio-nitrobenzoic acid (DTNB) to yield thio-nitrobenzoate which absorbs at 412 nm[41]. We analysed four different patien...

Reduced growth of patient fibroblasts in galactose. Fibroblast lines from four different patients and four healthy controls were cultured with either glucose (filled symbols) or galactose (open symbols) as a carbon source and confluency was measured with an Incucyte HD live cell imaging system. Patient-derived cells in galactose needed a mean value...

mtDNA variants in pedigrees II and III. Base indicates the position relative to the revised Cambridge reference sequence of human mitochondrial DNA; the GB frequency data is derived from 29,867 GenBank sequences with size greater than 15.4kbp and published on the MITOMAP database. A value of 1 indicates 100% prevalence [7]. (DOCX)

Muscle biopsy shows reduced complex I and IV activity. Biochemical analysis of skeletal muscle homogenate from a patient carrying the m.547A>T mutation showed that the activities of complexes I and IV are both outside the control range, while complexes II and III activities are normal. All enzyme activities are normalised for citrate synthase activ...

Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA cod...

Human induced pluripotent stem cell (hiPSC) utility is limited by variations in the ability of these cells to undergo lineage- specific differentiation. We have undertaken a transcriptional comparison of human embryonic stem cell (hESC) lines and hiPSC lines and have shown that hiPSCs are inferior in their ability to undergo neuroectodermal differe...

Background: Mitochondrial encephalomyopathies are severe, relentlessly progressive conditions and there are very few effective therapies available to date. We have previously suggested that in two rare forms of reversible mitochondrial disease (reversible infantile respiratory chain deficiency and reversible infantile hepatopathy) supplementation...

The exosome complex is the most important RNA processing machinery within the cell. Mutations in its subunits EXOSC8 and EXOSC3 cause pontocerebellar hypoplasia, spinal muscular atrophy (SMA) and central nervous system demyelination. We present a patient with SMA-like phenotype carrying a homozygous mutation in RBM7 - a subunit of the nuclear exoso...

Liver failure is a heterogeneous condition which may be fatal and the primary cause is frequently unknown. We investigated mitochondrial oxidative phosphorylation in patients undergoing liver transplantation. We studied 45 patients who had liver transplantation due to a variety of clinical presentations. Blue native polyacrylamide gel electrophores...

Background: Behr's syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties. Objective: Here we describe 4 patients with the classical Behr's syndrome phenotype fr...

Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the "missing heritability" of several complex traits. Given the central role...

Childhood-onset mitochondrial encephalomyopathies are severe, relentlessly progressive conditions. However reversible infantile respiratory chain deficiency (RIRCD), due to a homoplasmic mt-tRNA(Glu) mutation, and reversible infantile hepatopathy, due to tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency, stand out by show...

Multiple sclerosis is likely caused by a complex interaction of multiple genes and environmental factors. The contribution of mitochondrial DNA genetic backgrounds has been frequently reported. To evaluate the effect of mitochondrial DNA haplogroups in the same genetic and environmental circumstances, we have built human transmitochondrial cell lin...

Exome sequencing identified compound heterozygous mutations in the recently discovered mitochondrial methionyl-tRNA formyltransferase (MTFMT) gene in two sisters with mild Leigh syndrome and combined respiratory chain deficiency. The mutations lead to undetectable levels of the MTFMT protein. Blue native polyacrylamide gel electrophoresis showed de...

Some ribosomal antibiotics used in clinical practice to fight pathogenic bacteria can provoke serious adverse drug reactions in patients. Sensitivity to the antibiotics is a multifactorial trait but the genetic variation of sensitive individuals to off-target effects of the drugs might be one of the factors contributing to this condition. Thus, the...

Preclinical Research Several key components of the oxidative phosphorylation system are coded in mitochondrial DNA . In humans, the mutation rate of the mitochondrial genome is higher than that of nuclear DNA . Some of these mutations can modify the interaction of mitochondrial DNA ‐encoded products with different therapeutic drugs. Several of the...

Disorders resulting from mitochondrial DNA (mtDNA) mutations, including nonsense mutations, do not yet have causal treatments. As we discuss here, read-through therapies appear to be a promising approach to the treatment of disorders arising from nuclear DNA (nDNA) nonsense mutations. The genetics of mitochondrial DNA suggest that this therapy will...

Leber's hereditary optic neuropathy is a maternally inherited optic atrophy caused by mitochondrial DNA point mutations. Previous epidemiological studies have shown that individuals from mitochondrial genetic backgrounds (haplogroups) J/Uk and H have a higher and a lower risk, respectively, of suffering this disorder. To analyze the bases of these...

Egg yolk and milk are the 2 major membrane cryoprotectants commonly used in freezing media for the long-term preservation of semen (alone or in combination with others). However, in recent years, there have been increasing arguments against the use of egg yolk or milk because of the risk of introducing diseases through the use of cryopreserved seme...

A human mitochondrial DNA (mtDNA) transition, m.1555A>G, in the 12S rRNA gene causes non-syndromic hearing loss. However, this pathological mutation is the wild-type allele in orangutan mtDNA. Here we rule out different genetic factors as the reason for its fixation in orangutans and show that aminoglycosides negatively affect the oxidative phospho...

Genetic variation in human cytochrome b generates structurally different coenzyme Q binding pockets, affects the coupling efficiency of the oxidative phosphorylation system and susceptibility to different medical conditions. As modification of coupling efficiency has already been shown to have therapeutic interest, these structural differences migh...