Combination of common mtDNA variants results in mitochondrial dysfunction and a connective tissue dysregulation.

Mitochondrial dysfunction can be associated with a range of clinical manifestations. Here, we report a family with a complex phenotype including combinations of connective tissue, neurological, and metabolic symptoms that were passed on to all surviving children. Analysis of the maternally inherited mtDNA revealed a novel genotype encompassing the haplogroup J - defining mitochondrial DNA (mtDNA) ND5 m.13708G>A (A458T) variant arising on the mtDNA haplogroup H7A background, an extremely rare combination. Analysis of transmitochondrial cybrids with the 13708A-H7 mtDNA revealed a lower mitochondrial respiration, increased reactive oxygen species production (mROS), and dysregulation of connective tissue gene expression. The mitochondrial dysfunction was exacerbated by histamine, explaining why all eight surviving children inherited the dysfunctional histidine decarboxylase allele (W327X) from the father. Thus, certain combinations of common mtDNA variants can cause mitochondrial dysfunction, mitochondrial dysfunction can affect extracellular matrix gene expression, and histamine-activated mROS production can augment the severity of mitochondrial dysfunction. Most important, we have identified a previously unreported genetic cause of mitochondrial disorder arising from the incompatibility of common, nonpathogenic mtDNA variants.

Mitochondrial DNA and Alzheimer's disease: a first case-control study of the Tunisian population.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder in humans and presents a major health problem throughout the world. The etiology of AD is complex, and many factors are implicated, including mitochondria. Mitochondrial alteration has been proposed as a possible cause of AD. Therefore, several studies have focused on finding an association between inherited mitochondrial DNA variants and AD onset. METHODS: In this study, we looked, for the first time, for a potential association between mitochondrial haplogroups or polymorphisms and AD in the Tunisian population. We also evaluated the distribution of the major genetic risk factor for AD, the apolipoprotein E epsilon 4 (APOE ε4), in this population. In total, 159 single-nucleotide polymorphisms (SNPs) of mitochondrial DNA haplogroups were genotyped in 254 individuals (58 patients and 196 controls). An additional genotyping of APOE ε4 was performed. RESULTS: No significant association between mitochondrial haplogroups and AD was found. However, two individual SNPs, A5656G (p = 0.03821, OR = 10.46) and A13759G (p = 0.03719, OR = 10.78), showed a significant association with AD. APOE 4 was confirmed as a risk factor for AD (p = 0.000014). CONCLUSION: Our findings may confirm the absence of a relation between mitochondrial haplogroups and AD and support the possible involvement of some inherited variants in the pathogenicity of AD.

Mitochondrial polymorphism shapes intrapopulation behavioural variation in wild Drosophila.

Intrapopulation variation in behaviour, including activity, boldness and aggressiveness, is becoming more widely recognized and is hypothesized to substantially affect ecological and evolutionary dynamics. Although previous studies used candidate-gene approaches and genome-wide association analyses to identify genes correlated with variations in activity and aggressiveness, behavioural variation may not be fully captured in the nuclear genome, as it does not account for mitochondrial genomes. Mitochondrial genes encode products that are key regulators of the cellular energy-producing pathways in metabolic processes and are thought to play a significant role in life-history and reproductive traits. In this study, we considered many isofemale lines of Drosophila immigrans established from two wild populations to investigate whether intrapopulation variation in the mitochondrial genome affected activity level within this species. We identified two major haplogroups in these populations, and activity levels in both larvae and adults differed significantly between the two haplogroups. This result indicated that intrapopulation variation in activity level may be partially controlled by mitochondrial genes, along with the interaction between nuclear and mitochondrial genes and the age of individual organisms.

The alterations of mitochondrial DNA in coronary heart disease.

Coronary heart disease (CHD) is the major cause of death in modern society. CHD is characterized by atherosclerosis, which could lead to vascular cavity stenosis or obstruction, resulting in ischemic cardiac conditions such as angina and myocardial infarction. In terms of the mitochondrion, the main function is to produce adenosine triphosphate (ATP) for cells. And the alterations (including mutations, altered copy number and haplogroups) of mitochondrial DNA (mtDNA) are associated with the abnormal expression of oxidative phosphorylation (OXPHOS) system, resulting in mitochondrial dysfunction, then leading to perturbation on the electron transport chain and increased ROS generation and reduction in ATP level, contributing to ATP-producing disorders and oxidative stress, which may further accelerate development or vulnerability of atherosclerosis and myocardial ischemic injury. Therefore, the mtDNA defects may play an important role in making an early diagnosis, identifying disease-specific biomarkers and therapeutic targets, and predicting outcomes for patients with atherosclerosis and CHD. In this review, we aim to summarize the contribution of mtDNA mutations, altered mtDNA copy number and mtDNA haplogroups on the occurrence and development of CHD.

A simultaneous search for footprints of early human migration processes using the genetic and folk music data in Eurasia.

In this study, we aimed to illustrate the efficiency of correlation analysis of musical and genetic data for certain common ethnic and ethno-musical roots of mankind. The comparison of the results to archaeogenetic data shows that correlations of recent musical and genetic data may reveal past cultural and migration processes resulting in recent connections. The significance tests verified our hypothesis supposing that propagation of oral musical traditions can be related to early human migration processes is well-founded, because the multidimensional point system determined by the inverse rank vectors of correlating Hg-UCT pairs has a very clear structure. We found that associations of Hgs jointly propagating with associations of UCTs (Unified Contour Type) can be identified as significant complex components in both modern and ancient populations, thus, modern populations can be considered as admixtures of these ancient Hg associations. It also seems obvious to conclude that these ancient Hg associations strewed their musical "parent languages" during their migrations, and the correlating UCTs of these musical parent languages may also be basic components of the recent folk music cultures. Thus, we can draw a hypothetical picture of the main characteristics of ancient musical cultures. Modern and prehistoric populations belonging to a common Hg-UCT association are located to very similar geographical areas, consequently, recent folk music cultures are basically determined by prehistoric migrations. Our study could be considered as an initial step in analysis of the correlations of prehistoric and recent musical and genetic characteristics of human evolution history.

European mitochondrial haplogroups predict liver-related outcomes in patients coinfected with HIV and HCV: a retrospective study.

BACKGROUND: Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients. METHODS: We carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk. RESULTS: The study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups (p = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values. CONCLUSIONS: European mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

A new self-learning computational method for footprints of early human migration processes.

We present a new self-learning computational method searching for footprints of early migration processes determining the genetic compositions of recent human populations. The data being analysed are 26- and 18-dimensional mitochondrial and Y-chromosomal haplogroup distributions representing 50 recent and 34 ancient populations in Eurasia and America. The algorithms search for associations of haplogroups jointly propagating in a significant subset of these populations. Joint propagations of Hgs are detected directly by similar ranking lists of populations derived from Hg frequencies of the 50 Hg distributions. The method provides us the most characteristic associations of mitochondrial and Y-chromosomal haplogroups, and the set of populations where these associations propagate jointly. In addition, the typical ranking lists characterizing these Hg associations show the geographical distribution, the probable place of origin and the paths of their protection. Comparison to ancient data verifies that these recent geographical distributions refer to the most important prehistoric migrations supported by archaeological evidences.

mtDNA analysis of 174 Eurasian populations using a new iterative rank correlation method.

In this study, we analyse 27-dimensional mtDNA haplogroup distributions of 174 Eurasian, North-African and American populations, including numerous ancient data as well. The main contribution of this work was the description of the haplogroup distribution of recent and ancient populations as compounds of certain hypothetic ancient core populations immediately or indirectly determining the migration processes in Eurasia for a long time. To identify these core populations, we developed a new iterative algorithm determining clusters of the 27 mtDNA haplogroups studied having strong rank correlation among each other within a definite subset of the populations. Based on this study, the current Eurasian populations can be considered as compounds of three early core populations regarding to maternal lineages. We wanted to show that a simultaneous analysis of ancient and recent data using a new iterative rank correlation algorithm and the weighted SOC learning technique may reveal the most important and deterministic migration processes in the past. This technique allowed us to determine geographically, historically and linguistically well-interpretable clusters of our dataset having a very specific, hardly classifiable structure. The method was validated using a 2-dimensional stepping stone model.

Mitochondrial haplogroups and control region polymorphisms in Kaposi's sarcoma patients.

Inflammation and reactive oxygen species (ROS) production have recently considered as key mechanisms in the pathogenesis of Kaposi's sarcoma (KS). Since mitochondria are the major source of ROS production, this organelle may play a main role in KS development. However, there are no studies on mtDNA variations and haplogroups in this area. The focus of this study was to investigate the mtDNA variants and haplogroups in KS patients and their relationship to tumor development. To address this, we have genotyped mtDNA in 45 Iranian KS patients and 48 age and sex-matched Iranian controls. A strong positive correlation was observed between UK cluster and decreased risk of KS. Our results suggest that the UK cluster might be a protective haplogroup for KS development. It is probably superhaplogroup UK, with lower ATP and ROS production, may prevent KSHV reactivation from latent to lytic phase that is essential for KS development.

The impact of mitochondrial DNA and nuclear genes related to mitochondrial functioning on the risk of Parkinson's disease.

Mitochondrial dysfunction and oxidative stress are the major factors implicated in Parkinson's disease (PD) pathogenesis. The maintenance of healthy mitochondria is a very complex process coordinated bi-genomically. Here, we review association studies on mitochondrial haplogroups and subhaplogroups, discussing the underlying molecular mechanisms. We also focus on variation in the nuclear genes (NDUFV2, PGC-1alpha, HSPA9, LRPPRC, MTIF3, POLG1, and TFAM encoding NADH dehydrogenase (ubiquinone) flavoprotein 2, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, mortalin, leucine-rich pentatricopeptide repeat containing protein, translation initiation factor 3, mitochondrial DNA polymerase gamma, and mitochondrial transcription factor A, respectively) primarily linked to regulation of mitochondrial functioning that recently have been associated with PD risk. Possible interactions between mitochondrial and nuclear genetic variants and related proteins are discussed.

Genetic and phenotypic associations of mitochondrial DNA copy number, SNP, and haplogroups with growth and carcass traits in beef cattle.

Mitochondrial DNA copy number (mtDNA CN) is heritable and easily obtained from low-pass sequencing (LPS). This study investigated the genetic correlation of mtDNA CN with growth and carcass traits in a multi-breed and crossbred beef cattle population. Blood, leucocyte, and semen samples were obtained from 2,371 animals and subjected to LPS that resulted in nuclear DNA (nuDNA) and mtDNA sequence reads. Mitochondrial DNA CN was estimated as the ratio of mtDNA to nuDNA coverages. Variant calling was performed from mtDNA, and 11 single nucleotide polymorphisms (SNP) were identified in the population. Samples were classified in taurine haplogroups. Haplogroup and mtDNA type were further classified based on the 11 segregating SNP. Growth and carcass traits were available for between 7,249 and 60,989 individuals. Associations of mtDNA CN, mtDNA haplogroups, mtDNA types, and mtDNA SNP with growth and carcass traits were estimated with univariate animal models, and genetic correlations were estimated with a bivariate animal model based on pedigree. Mitochondrial DNA CN tended (P-value ≤0.08) to be associated with birth weight and weaning weight. There was no association (P-value >0.10) between mtDNA SNP, haplogroups, or types with growth and carcass traits. Genetic correlation estimates of mtDNA CN were -0.30 ± 0.16 with birth weight, -0.31 ± 0.16 with weaning weight, -0.15 ± 0.14 with post-weaning gain, -0.11 ± 0.19 with average daily dry-matter intake, -0.04 ± 0.22 with average daily gain, -0.29 ± 0.13 with mature cow weight, -0.11 ± 0.13 with slaughter weight, -0.14 ± 0.13 with carcass weight, -0.07 ± 0.14 with carcass backfat, 0.14 ± 0.14 with carcass marbling, and -0.06 ± 0.14 with ribeye area. In conclusion, mtDNA CN was negatively correlated with most traits investigated, and the genetic correlation was stronger with growth traits than with carcass traits.

This study investigated mitochondrial DNA copy number (mtDNA CN) as a potential genetic indicator of growth and carcass traits in a composite beef cattle population. Mitochondrial DNA CN was previously shown to be under genetic control. The current study estimated the genetic relationship of mtDNA CN with growth and carcass traits. Blood, leucocyte, and semen samples were obtained from 2,371 animals and subjected to whole-genome sequencing at a low depth that resulted in nuclear DNA and mtDNA sequence reads. Mitochondrial DNA CN was estimated as the ratio of mtDNA to nuclear DNA coverages. Growth and carcass traits were available for between 7,249 and 60,989 individuals. Genetic parameters were estimated from an animal model based on pedigree. Genetic correlation estimates of mtDNA CN with growth and carcass traits were low to moderate and mostly negative. These indicate that selection for lower mtDNA would be associated with an increase in birth weight, weaning weight, post-weaning gain, average daily dry-matter intake, mature cow weight, slaughter weight, and carcass weight. Therefore, the by-product of whole-genome sequencing at a low depth could be used as an indicator trait for growth and carcass traits in genetic evaluations, but the genetic relationships are not likely strong enough to prioritize mtDNA ahead of routinely used indicator traits.

Sexual Orientation in Twins: Evidence That Human Sexual Identity May Be Determined Five Days Following Fertilization.

Human same-sex sexual attraction has been recorded from the beginning of written history. It remains a controversial topic, but recent theories favor prenatal influences. A paradox is the occurrence of same-sex orientation in twins in that there is a higher level of concordance in monozygous twins compared to that in dizygous twins or non-twin siblings. If sexual orientation was entirely genetically determined monozygous twins would be expected to have identical sexual inclinations. Monozygous twins have twice the incidence of sexual concordance in comparison to dizygous twins but a third of these pairs have different sexual identities. An explanation for this disparity may lie in the time an embryo splits to form two separate fetuses. If splitting occurs early in twin development each twin may develop his or her own sexual identity; splitting occurring later results in twins that have the same sexual dispositions. A possible process for such determination may be in the mitochondria, with universal maternal inheritance of a proportion of normal functioning but alternate mitochondria. Variation in the distribution of these mitochondria in neural precursor cells becomes a mechanism for the development of intrinsic sexual orientation and for the spectrum of human sexual inclinations. The timing of embryonic splitting may be determined from the examination of fetal membranes, and the concept of early fetal sexual orientation is open to support or disproval.

Impacts of Bacteriostatic and Bactericidal Antibiotics on the Mitochondria of the Age-Related Macular Degeneration Cybrid Cell Lines.

We assessed the potential negative effects of bacteriostatic and bactericidal antibiotics on the AMD cybrid cell lines (K, U and J haplogroups). AMD cybrid cells were created and cultured in 96-well plates and treated with tetracycline (TETRA) and ciprofloxacin (CPFX) for 24 h. Reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔψM), cellular metabolism and ratio of apoptotic cells were measured using H2DCFDA, JC1, MTT and flow cytometry assays, respectively. Expression of genes of antioxidant enzymes, and pro-inflammatory and pro-apoptotic pathways were evaluated by quantitative real-time PCR (qRT-PCR). Higher ROS levels were found in U haplogroup cybrids when treated with CPFX 60 µg/mL concentrations, lower ΔψM of all haplogroups by CPFX 120 µg/mL, diminished cellular metabolism in all cybrids with CPFX 120 µg/mL, and higher ratio of dead cells in K and J cybrids. CPFX 120 µg/mL induced overexpression of IL-33, CASP-3 and CASP-9 in all cybrids, upregulation of TGF-ß1 and SOD2 in U and J cybrids, respectively, along with decreased expression of IL-6 in J cybrids. TETRA 120 µg/mL induced decreased ROS levels in U and J cybrids, increased cellular metabolism of treated U cybrids, higher ratio of dead cells in K and J cybrids and declined ΔψM via all TETRA concentrations in all haplogroups. TETRA 120 µg/mL caused upregulation of IL-6 and CASP-3 genes in all cybrids, higher CASP-7 gene expression in K and U cybrids and downregulation of the SOD3 gene in K and U cybrids. Clinically relevant dosages of ciprofloxacin and tetracycline have potential adverse impacts on AMD cybrids possessing K, J and U mtDNA haplogroups in vitro.

Mitochondrial DNA Footprints from Western Eurasia in Modern Mongolia.

Mongolia is located in a strategic position at the eastern edge of the Eurasian Steppe. Nomadic populations moved across this wide area for millennia before developing more sedentary communities, extended empires, and complex trading networks, which connected western Eurasia and eastern Asia until the late Medieval period. We provided a fine-grained portrait of the mitochondrial DNA (mtDNA) variation observed in present-day Mongolians and capable of revealing gene flows and other demographic processes that took place in Inner Asia, as well as in western Eurasia. The analyses of a novel dataset (N = 2,420) of mtDNAs highlighted a clear matrilineal differentiation within the country due to a mixture of haplotypes with eastern Asian (EAs) and western Eurasian (WEu) origins, which were differentially lost and preserved. In a wider genetic context, the prevalent EAs contribution, larger in eastern and central Mongolian regions, revealed continuous connections with neighboring Asian populations until recent times, as attested by the geographically restricted haplotype-sharing likely facilitated by the Genghis Khan's so-called Pax Mongolica. The genetic history beyond the WEu haplogroups, notably detectable on both sides of Mongolia, was more difficult to explain. For this reason, we moved to the analysis of entire mitogenomes (N = 147). Although it was not completely possible to identify specific lineages that evolved in situ, two major changes in the effective (female) population size were reconstructed. The more recent one, which began during the late Pleistocene glacial period and became steeper in the early Holocene, was probably the outcome of demographic events connected to western Eurasia. The Neolithic growth could be easily explained by the diffusion of dairy pastoralism, as already proposed, while the late glacial increase indicates, for the first time, a genetic connection with western Eurasian refuges, as supported by the unusual high frequency and internal sub-structure in Mongolia of haplogroup H1, a well-known post-glacial marker in Europe. Bronze Age events, without a significant demographic impact, might explain the age of some mtDNA haplogroups. Finally, a diachronic comparison with available ancient mtDNAs made it possible to link six mitochondrial lineages of present-day Mongolians to the timeframe and geographic path of the Silk Route.

Pilot Screening of Cell-Free mtDNA in NIPT: Quality Control, Variant Calling, and Haplogroup Determination.

Clinical tests based on whole-genome sequencing are generally focused on a single task approach, testing one or several parameters, although whole-genome sequencing (WGS) provides us with large data sets that can be used for many supportive analyses. In spite of low genome coverage, data of WGS-based non-invasive prenatal testing (NIPT) contain fully sequenced mitochondrial DNA (mtDNA). This mtDNA can be used for variant calling, ancestry analysis, population studies and other approaches that extend NIPT functionality. In this study, we analyse mtDNA pool from 645 cell-free DNA (cfDNA) samples of pregnant women from different regions of Russia, explore the effects of transportation and storing conditions on mtDNA content, analyse effects, frequency and location of mitochondrial variants called from samples and perform haplogroup analysis, revealing the most common mitochondrial superclades. We have shown that, despite the relatively low sequencing depth of unamplified mtDNA from cfDNA samples, the mtDNA analysis in these samples is still an informative instrument suitable for research and screening purposes.

Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups.

BACKGROUND: Drug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual's mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual's mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations. METHODS: The present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels for ALK, BRCA1, EGFR, and ERBB2/HER2. RESULTS: Results indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%, p < 0.012) < D (24.86%, p = 0.0001) and [A+B] cybrids (24.67%, p = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B], p = 0.0270). (4) The expression levels decreased for ALK in L (p < 0.0001) and [A+B] (p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased for EGFR in [A+B] cybrids (p = 0.0246) compared to untreated cybrids. CONCLUSION: Our findings suggest that an individual's mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment.

Role of mitochondrial DNA variants in the development of fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in at least one-third of adult carriers of FMR1 premutation. Several studies have shown that mitochondrial dysfunction may play a role in neurodegenerative disorders. In order to assess whether mitochondrial DNA variants are involved in the risk of developing FXTAS we evaluated the frequency of mitochondrial haplogroups in 132 unrelated Spanish FMR1 premutation carriers. In addition, the entire mitogenome of 26 FMR1 premutation carriers was sequenced using massively parallel sequencing technologies to analyze mitochondrial DNA variants. Statistical analyses reveal a significant difference in the frequency of T haplogroup. Data analysis of mitochondrial DNA sequences evidence an association between FXTAS and the burden of heteroplasmic variants as well as their distribution. Our results suggest that haplogroup T might be a potential protective factor for FXTAS and that FXTAS individuals accumulate higher rates of heteroplasmic variants in compromised regions of the mitochondrial genome. These results may explain, in part, the role of mitochondrial DNA in the development of FXTAS.

European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects.

Background: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will become resistant. Mitochondria play a significant role not only in energy metabolism but also retrograde signaling (mitochondria to nucleus) that modulates inflammation, complement, and apoptosis pathways. Maternally inherited mitochondrial (mt) DNA can be classified into haplogroups representing different ethnic populations that have diverse susceptibilities to diseases and medications. Methods: Transmitochondrial cybrids, where all cell lines possess identical nuclear genomes but either the H (Southern European) or J (Northern European) mtDNA haplogroups, were treated with cisplatin and analyzed for differential responses related to viability, oxidative stress, and expression levels of genes associated with cancer, cisplatin-induced nephrotoxicity and resistance, apoptosis and signaling pathways. Results: The cisplatin-treated-J cybrids showed greater loss of cell viability along with lower levels of reactive oxygen species and mitochondrial membrane potential compared to cisplatin-treated-H cybrids. After cisplatin treatment, J cybrids showed increased gene expression of BAX, CASP3, and CYP51A, but lower levels of SFRP1 compared to untreated-J cybrids. The cisplatin-treated-H cybrids had elevated expression of CDKN1A/P21, which has a role in cisplatin toxicity, compared to untreated-H cybrids. The cisplatin-treated H had higher transcription levels of ABCC1, DHRS2/HEP27, and EFEMP1 compared to cisplatin-treated-J cybrids. Conclusions: Cybrid cell lines that contain identical nuclei but either H mtDNA mitochondria or J mtDNA mitochondria respond differently to cisplatin treatments suggesting involvement of the retrograde signaling (from mitochondria to nucleus) in the drug-induced cell death. Varying toxicities and transcription levels of the H vs. J cybrids after cisplatin treatment support the hypothesis that mtDNA variants play a role in the expression of genes affecting resistance and side effects of cisplatin.

Involvement of mitochondrial haplogroups in myocardial infarction and stroke: A case-control study in Castile and Leon (Spain) population.

There are strong evidences that common mitochondrial DNA (mtDNA) haplogroups may influence the pathogenesis of cardiovascular diseases (CVDs). In this matched case-control study, we investigate the association between mtDNA haplogroups and two CVDs, myocardial infarction (MI) and stroke, and classical cardiovascular risk factors. Data obtained show that haplogroup H constitute a susceptibility risk factor for MI (p=0.001; OR=2.379, 95% CI [1.440-3.990]). Otherwise, our data also suggest a beneficial role of haplogroup J against hypertension (p=0.019; OR=0.348, 95% CI [0.144-0.840]). These results may provide some guidance for predicting the genetic risk of these diseases in different human populations through the differences in energy efficiency between haplogroups.

Is mitochondrial DNA profiling predictive for athletic performance?

Mitochondrial DNA encodes some proteins of the oxidative phosphorylation enzymatic complex, playing an important role in aerobic ATP production; therefore, it can contribute to the ability to respond to endurance exercise training. The accumulation of mitochondrial mutations and the migratory processes of populations have given a great contribution to the development of haplogroups with a different distribution in the world. Several studies have shown the important role of gene polymorphisms in aerobic performance. In this review, some mitochondrial haplogroups and multiple rare alleles were taken into consideration and could be linked to the athlete's physical performance of different ethnic groups.