Mitochondrial DNA Alterations Research Articles

Altered Mitochondrial DNA Copy Number and Telomere Length in Patients with Substance Use Disorder: Correlation with Age, Sex, and Chronic Diseases.

Substance use disorder (SUD) is a complex condition involving psychological, sociocultural, and genetic factors. In this study, we examined the alternations in mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) and their relationship to demographic, medical, heredity, and substance use characteristics in patients with SUD and healthy controls. We investigated a total cohort of 54 participants: 21 healthy individuals, 17 patients with alcohol dependence (AD), and 16 patients with drug dependence (DD). TL and mtDNAcn were measured using quantitative real-time PCR, with statistical methods used to assess the association between variables. We observed a significant decrease in mtDNAcn in both SUD groups, particularly associated with chronic diseases in the AD group. No significant differences in TL were found among the three groups. Sex-associated analysis revealed a significant mtDNAcn reduction in the DD males and elevated TL in AD males compared to control males. Correlation analyses showed associations between the two biomarkers and age, sex, and chronic diseases. Our findings suggest that leukocyte mtDNAcn is a more sensitive marker than TL in patients with SUD, indicating sex-specific patterns of alterations. These findings require confirmation through larger cohort recruitment.

Deep learning-enhanced automated mitochondrial segmentation in FIB-SEM images using an entropy-weighted ensemble approach.

Mitochondria are intracellular organelles that act as powerhouses by breaking down nutrition molecules to produce adenosine triphosphate (ATP) as cellular fuel. They have their own genetic material called mitochondrial DNA. Alterations in mitochondrial DNA can result in primary mitochondrial diseases, including neurodegenerative disorders. Early detection of these abnormalities is crucial in slowing disease progression. With recent advances in data acquisition techniques such as focused ion beam scanning electron microscopy, it has become feasible to capture large intracellular organelle volumes at data rates reaching 4Tb/minute, each containing numerous cells. However, manually segmenting large data volumes (gigapixels) can be time-consuming for pathologists. Therefore, there is an urgent need for automated tools that can efficiently segment mitochondria with minimal user intervention. Our article proposes an ensemble of two automatic segmentation pipelines to predict regions of interest specific to mitochondria. This architecture combines the predicted outputs from both pipelines using an ensemble learning-based entropy-weighted fusion technique. The methodology minimizes the impact of individual predictions and enhances the overall segmentation results. The performance of the segmentation task is evaluated using various metrics, ensuring the reliability of our results. We used four publicly available datasets to evaluate our proposed method's effectiveness. Our proposed fusion method has achieved a high score in terms of the mean Jaccard index and dice coefficient for all four datasets. For instance, in the UroCell dataset, our proposed fusion method achieved scores of 0.9644 for the mean Jaccard index and 0.9749 for the Dice coefficient. The mean error rate and pixel accuracy were 0.0062 and 0.9938, respectively. Later, we compared it with state-of-the-art methods like 2D and 3D CNN algorithms. Our ensemble approach shows promising segmentation efficiency with minimal intervention and can potentially aid in the early detection and mitigation of mitochondrial diseases.

Best practices for germline variant and DNA methylation analysis of second- and third-generation sequencing data.

This comprehensive review provides insights and suggested strategies for the analysis of germline variants using second- and third-generation sequencing technologies (SGS and TGS). It addresses the critical stages of data processing, starting from alignment and preprocessing to quality control, variant calling, and the removal of artifacts. The document emphasized the importance of meticulous data handling, highlighting advanced methodologies for annotating variants and identifying structural variations and methylated DNA sites. Special attention is given to the inspection of problematic variants, a step that is crucial for ensuring the accuracy of the analysis, particularly in clinical settings where genetic diagnostics can inform patient care. Additionally, the document covers the use of various bioinformatics tools and software that enhance the precision and reliability of these analyses. It outlines best practices for the annotation of variants, including considerations for problematic genetic alterations such as those in the human leukocyte antigen region, runs of homozygosity, and mitochondrial DNA alterations. The document also explores the complexities associated with identifying structural variants and copy number variations, underscoring the challenges posed by these large-scale genomic alterations. The objective is to offer a comprehensive framework for researchers and clinicians, ensuring that genetic analyses conducted with SGS and TGS are both accurate and reproducible. By following these best practices, the document aims to increase the diagnostic accuracy for hereditary diseases, facilitating early diagnosis, prevention, and personalized treatment strategies. This review serves as a valuable resource for both novices and experts in the field, providing insights into the latest advancements and methodologies in genetic analysis. It also aims to encourage the adoption of these practices in diverse research and clinical contexts, promoting consistency and reliability across studies.

Mitoepigenetics pathways and natural compounds: a dual approach to combatting hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading liver cancer that significantly impacts global life expectancy and remains challenging to treat due to often late diagnoses. Despite advances in treatment, the prognosis is still poor, especially in advanced stages. Studies have pointed out that investigations into the molecular mechanisms underlying HCC, including mitochondrial dysfunction and epigenetic regulators, are potentially important targets for diagnosis and therapy. Mitoepigenetics, or the epigenetic modifications of mitochondrial DNA, have drawn wide attention for their role in HCC progression. Besides, molecular biomarkers such as mitochondrial DNA alterations and non-coding RNAs showed early diagnosis and prognosis potential. Additionally, natural compounds like alkaloids, resveratrol, curcumin, and flavonoids show promise in HCC show promise in modulating mitochondrial and epigenetic pathways involved in cancer-related processes. This review discusses how mitochondrial dysfunction and epigenetic modifications, especially mitoepigenetics, influence HCC and delves into the potential of natural products as new adjuvant treatments against HCC.

Mitochondrial DNA Alterations in Glioblastoma and Current Therapeutic Targets.

Metabolic reprogramming within tumor cells involves a shift towards either glycolysis or mitochondrial respiration, depending on the stage of tumor progression. Consequently, irreversible dysfunction of the mitochondria is considered a crucial mechanism driving the progression mechanism. While numerous mutations in mitochondrial DNA (mtDNA) have been identified across various tumor types, including glioblastoma, many studies have been limited in the scope, focusing on small segments of mtDNA or utilizing sequencing methods with restricted sensitivity. As a result, several potentially significant mtDNA mutations may have been underestimated, along with their heteroplasmic states, which play a crucial role in determining the phenotypic impact of mtDNA mutation. Although both somatic and germline mtDNA mutations have been observed in different tumor types, research on the mtDNA mutations linked to glioblastoma remains scarce. The mitochondrial genome encodes thirteen protein-coding genes that are essential for the proper functioning of respiratory complex chains. Alterations in mitochondrial function manifest at various levels, including structural and functional changes, impacting mitogenic, hemodynamic, bioenergetic, and apoptotic signaling pathways. These alterations often signify a reduced efficiency of the oxidative phosphorylation system and energy production in tumor cells. As the crucial role of mitochondrial dysfunction in glioma development grows, mitochondria have emerged as promising targets for therapy aimed at overcoming chemoresistance and eliminating cancer cells. This brief review outlines the association between mtDNA alteration and glioblastoma, as well as the current advancements in therapeutic strategies targeting mtDNA alterations.

Mitochondrial neurogastrointestinal encephalopathy: a case report

BackgroundMitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disease associated with alterations in mitochondrial DNA (mtDNA). The typical age of onset of MNGIE is between the first and second decade of life. Diagnosis requires the presence of several key clinical features: sensorimotor neuropathy, external ophthalmoplegia, ocular ptosis, leukoencephalopathy, and gastrointestinal (GI) dysmotility. Unfortunately, MNGIE diagnosis is very challenging, and patients often undergo multiple diagnostic and surgical operations that are unnecessary.Case presentationThis case is of a 51-year-old male presenting with a 2-year history of limb weakness, GI problems and cachexia. There was also a 1-year history of progressive ptosis and ophthalmoplegia. The patient’s uncle and brother had both died from GI-related issues prior to the age of 40. On physical examination, ocular motility was impaired in all directions and there was atrophy and reduction in power in both lower and upper extremities. FLAIR and T2-weighted sequences of brain MRI demonstrated diffuse cerebral white matter hyperintensity (leukoencephalopathy). On discharge, the patient was referred for genetic consultation for bone marrow transplantation and had regular follow-up with a gastroenterology specialist.ConclusionIn patients presenting with chronic progressive ophthalmoplegia, severe gastrointestinal complications, sensorimotor neuropathy and white matter lesions on MRI, it is important to consider investigating for MNGIE.

Association between mitochondrial DNA genotype and sperm motility in humans

The relationship between genetic alterations in mitochondrial DNA (mtDNA) and progressive motility (PR) and rapid progressive motility (grade A) of ejaculated human spermatozoa remains unclear. In this study, we explored the association between human mtDNA genotype and sperm PR and grade A by analyzing mtDNA copy number, loci, haplogroup, rearrangement, deletions, and duplications and sperm motility parameters. Human sperm mtDNA copy number, loci and haplogroups were not associated with human sperm motility PR or A grade. However, the cumulative frequency of human sperm mtDNA rearrangements (including deletions and duplications) in participants with high PR and grade A ratio was higher than in participants with low PR and grade A ratio. Additional studies are needed to understand the relationship between mtDNA genotypes, including deletions and duplications, and human sperm motility.

Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control.

Mitochondrial Deoxyribonucleic Acid Copy Number Elevation As a Predictor for Extended Survival and Favorable Outcomes in High-Grade Brain Tumor Patients: A Malaysian Study.

Investigating the role of mitochondrial DNA (mtDNA) alterations and their impact on brain tumor progression remains a significant focus in cancer research. The research aimed to explore the specific contributions of mtDNA copy number changes and their correlations with patient survival, large mtDNA deletions, and TFAM mutations in brain tumor patients. A total of 41 patients with confirmed brain tumors underwent DNA extraction from both tumor tissues and blood samples. The relative mtDNA copy number in comparison to the nuclear genome was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Long-range PCR assessed largescale mtDNA deletions, and Sanger sequencing was applied to detect exon 4 TFAM mutations. Analysis revealed significantly increased mtDNA copy numbers in brain tumor tissues (80.5%) compared to matched blood samples (P < .001). Median delta Ct (∆Ct) values were 7.35 in cancerous tissues and 11.81 in blood (P <.001), with median relative mtDNA content of 0.0123 and 0.0006, respectively (P <.001). Patients with higher mtDNA copy numbers experienced longer overall survival periods (P=.045) and notably favorable outcomes, particularly in high-grade tumor cases (P=.016). Furthermore, a singlenucleotide deletion was identified in exon 4 of TFAM in a patient with glioblastoma IV, while no large-scale mtDNA deletions were found in brain tumor patients. Our study strongly supports the role of increased mtDNA copy numbers as a reliable predictor for improved survival and positive outcomes in high-grade brain tumor patients.

Mitochondrial dysfunction and therapeutic perspectives in osteoporosis.

Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and structural deterioration of bone tissue, resulting in heightened vulnerability to fractures due to increased bone fragility. This condition primarily arises from an imbalance between the processes of bone resorption and formation. Mitochondrial dysfunction has been reported to potentially constitute one of the most crucial mechanisms influencing the pathogenesis of osteoporosis. In essence, mitochondria play a crucial role in maintaining the delicate equilibrium between bone formation and resorption, thereby ensuring optimal skeletal health. Nevertheless, disruption of this delicate balance can arise as a consequence of mitochondrial dysfunction. In dysfunctional mitochondria, the mitochondrial electron transport chain (ETC) becomes uncoupled, resulting in reduced ATP synthesis and increased generation of reactive oxygen species (ROS). Reinforcement of mitochondrial dysfunction is further exacerbated by the accumulation of aberrant mitochondria. In this review, we investigated and analyzed the correlation between mitochondrial dysfunction, encompassing mitochondrial DNA (mtDNA) alterations, oxidative phosphorylation (OXPHOS) impairment, mitophagy dysregulation, defects in mitochondrial biogenesis and dynamics, as well as excessive ROS accumulation, with regards to OP (Figure1). Furthermore, we explore prospective strategies currently available for modulating mitochondria to ameliorate osteoporosis. Undoubtedly, certain therapeutic strategies still require further investigation to ensure their safety and efficacy as clinical treatments. However, from a mitochondrial perspective, the potential for establishing effective and safe therapeutic approaches for osteoporosis appears promising.

Mitochondrial Chronic Progressive External Ophthalmoplegia.

Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management. This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought. CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies. Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.

Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells.

Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 μM and 200 μM of hydrogen peroxide (H2O2) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H2O2 and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H2O2 was also found. In PBMCs treated with 200 µM H2O2, a significant inverse correlation was found between TL and MN (r = -0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = -0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere-mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs.

Analysis for Mitochondrial Encoded Transfer RNA Leucine2 (MT-TL2) Gene in Breast Cancer Patients

Background: Breast cancer (BC) has been linked to a variety of nuclear DNA changes as well as mitochondrial DNA (mtDNA) alterations. The study aims to evaluate/analyze the association of mitochondrial transfer RNA (mt-tRNA) leucine 2 gene with BC patients. Methods: In the current study, 24 samples have been collected from various families in Peshawar. DNA was extracted from blood. Polymerase chain reaction was used to amplify the mt-tRNA MT-TL2 gene, and 20 samples were sequenced. Results: The sequence was compared with accession #NC-012920.1 of the Revised Cambridge Reference Sequence (rCRS). The results (chromatograph, nucleotide sequence, and rCRS alignment) show mutations in mt-tRNA MT-TL2 gene in our participants is not the cause of BC. Conclusion: Yet, a significant number of BC patients must be studied, and their full mtDNA must be analyzed. This will provide an indication of the potential DNA marker that might be used to prevent BC deaths at the earliest stages.

Altered Mitochondrial DNA Methylation Patterns in Thrombosis

DNA methylation being one of the chief controllers of gene expression has not only been the reason behind the initiation of a plethora of diseases like Cancer, Alzheimer’s disease, Parkinson’s disease, etc. Still, it is an active contributor to the pathophysiology of several cardiovascular diseases like coronary artery disease (CAD), Atherosclerosis, Stroke, Cardiomyopathy, etc. The role of nuclear DNA methylation in VTE has been studied earlier, but the comparison of methylation in both nuclear genes and mitochondrial genes in high altitude VTE (HA-VTE) and sea level VTE (SL-VTE) patients has not been studied in depth. Through this present study, DNA methylation patterns of mitochondrial encoded as well as nuclear-encoded mitochondrial genes of five high-altitude VTE patients and five sea-level VTE patients have been obtained. On comparing HA-VTE vs. SL-VTE methylation, one hundred and twenty hypermethylated genes and one hundred and thirty-eight hypomethylated genes were observed. Post gene enrichment and ontology study, the TCA cycle and NADH dehydrogenase were found to be the highly enriched pathways in both the study groups. Protein-protein interaction network using STRING pointed out the enriched pathway of L-2-hydroxyglutaric acid when both the gene sets were enriched. These results show the crucial role of mitochondrial DNA methylation in the pathophysiology of thrombosis and show great potential to study the role of mitochondria in thrombosis.

Exploiting nuclear-mitochondrial cross-talk in theranostics: Enhancing drug delivery and diagnostic precision

The dynamic interplay between nuclear and mitochondrial processes plays a pivotal role in cellular homeostasis and disease progression. Exploiting this nuclear-mitochondrial cross-talk has emerged as a promising avenue in the field of theranostics, offering enhanced drug delivery and diagnostic precision for a wide range of medical conditions, particularly cancer. This abstract provides a brief overview of the key concepts and recent advancements in this rapidly evolving field. Recent research has elucidated the significance of mitochondrial dysfunction in various diseases, including cancer. Mitochondria, often referred to as the “powerhouses” of the cell, not only regulate energy production but also contribute to critical processes such as apoptosis, ROS generation, and metabolic signaling. Dysregulation of these mitochondrial functions is frequently associated with disease pathogenesis. In theranostics, the targeted modulation of mitochondrial function holds great promise. Mitochondria-targeted drug delivery systems have been designed to selectively deliver therapeutic agents to these organelles, thereby mitigating mitochondrial dysfunction while minimizing off-target effects. This precise drug delivery enhances the therapeutic efficacy of anticancer drugs and reduces the risk of drug resistance. Moreover, the diagnostic potential of nuclear-mitochondrial cross-talk is being harnessed to develop novel biomarkers and imaging techniques. Mitochondrial DNA mutations and alterations in mitochondrial metabolism serve as valuable indicators of disease progression and drug responsiveness. Non-invasive imaging modalities, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have been employed to visualize mitochondrial activity and assess therapeutic outcomes.

Green synthesis of iron oxide nanoparticles from Spermacoce ocymoides Burm.f. plant extracts for targeted lung cancer A549 cell therapy

The present study evaluated the synthesis of iron oxide nanoparticles using Spermacoce ocymoides Burm.f. plant extracts, and the effects of plant based iron oxide nanoparticles on A549 lung cancer cells were investigated to elucidate their impact on cellular morphology, mitochondrial function, and apoptotic pathways. Spermacoce ocymoides plant based iron oxide nanoparticles were characterised by X-ray diffraction, Atomic force microscopy, FTIR, and UV-Vis absorption spectroscopy. Iron oxide nanoparticle treatment caused considerable morphological alterations in A549 cells, including cell shrinkage, detachment, membrane blabbing, and distorted shape, consistent with cellular stress and potential apoptotic events. MMP analysis revealed a dose-dependent decrease in mitochondrial membrane potential, implying that nanoparticles have an effect on mitochondrial function. The presence of reactive oxygen species suggested that oxidative stress was involved in the cellular response to iron oxide nanoparticles. Additionally, DNA fragmentation analysis confirmed the activation of apoptotic pathways, with the nanoparticles themselves serving as a positive control for inducing apoptosis. The observed morphological changes, altered mitochondrial function, ROS production, and DNA fragmentation collectively point towards apoptotic cell death pathways being triggered by the nanoparticles.&#x0D; KEY WORDS: Spermacoce ocymoides, Iron oxide nanoparticles, A549 cells, Apoptotic&#x0D; Bull. Chem. Soc. Ethiop. 2024, 38(1), 123-134. DOI: https://dx.doi.org/10.4314/bcse.v38i1.10

Altered mitochondrial DNA copy number in cervical exfoliated cells among high‑risk HPV‑positive and HPV‑negative women.

The majority of cervical cancer cases are due to human papillomavirus (HPV) infection. However, certain cases of cervical cancer are not caused by HPV. Recent studies have shown a link between altered mitochondrial DNA (mtDNA) copy number, an indicative measure of mitochondrial dysfunction, and cervical cancer in women who test positive for HPV. However, the role of the mtDNA copy number in HPV-negative cervical cancer has remained elusive. In the present study, the mtDNA copy number was determined using quantitative PCR as the ratio between mtDNA and nuclear DNA in 287 ThinPrep cervical samples, including 143 cases with cervical abnormalities and 144 control subjects with high-risk (hr)-HPV positive or HPV-negative status. In an overall analysis of cases categorized based on the cytology diagnosis into squamous cervical carcinoma/high-grade squamous intraepithelial lesions (SCC/HSIL), low-grade squamous intraepithelial lesions (LSIL) and normal controls, the mtDNA copy number was significantly higher in all cases compared to the controls and a higher mtDNA copy number was observed in SCC/HSIL compared to LSIL cases. In the stratification analyses based on hr-HPV positive and HPV-negative status, an increased mtDNA copy number was observed in the cases compared with the controls regardless of their HPV status (P<0.05). When cases with cervical abnormalities were categorized based on histological diagnosis into cervical intraepithelial neoplasia (CIN)2/CIN3 and CIN1, an overall analysis indicated an increased mtDNA copy number in CIN2/CIN3 compared to CIN1 (P=0.01). Stratification analyses of these cases based on HPV status revealed a higher mtDNA copy number in CIN2/CIN3 compared to CIN1 regardless of HPV infection (P<0.05). These results showed that an elevated mtDNA copy number in subjects with cervical abnormalities was not influenced by the HPV status and suggested the possibility of its role in the progression of cervical cancer. The increased mtDNA copy number may be an adaptive response mechanism to compensate for mtDNA oxidative stress and energy deficiency, possibly induced by HPV infection and other environmental exposures.

Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome.

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated. We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud's symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients. All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR. SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity. Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes.

Mitochondrial DNA copy number in autism spectrum disorder and attention deficit hyperactivity disorder: a systematic review and meta-analysis.

Several reports suggest that altered mitochondrial DNA copy number (mtDNA-cn), a common biomarker for aberrant mitochondrial function, is implicated in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), but the results are still elusive. A meta-analysis was performed to summarize the current indication and to provide a more precise assessment of the mtDNA-cn in ASD and ADHD. A search in the MEDLINE-PubMed, Scopus, and EMBASE databases was done to identify related studies up to the end of February 2023. The meta-analysis was conducted according to recommendations of the Cochrane Handbook of Systematic Reviews. Fourteen studies involving 666 cases with ASD and ADHD and 585 controls were collected and judged relevant for the systematic review and meta-analysis. The pooled results by a random effects meta-analysis was reported as a geometric mean of the estimated average response ratio and 95% confidence interval. Overall analysis of studies reported differences in mtDNA-cn in blood samples (k = 10) and non-blood samples (brain tissues and oral samples; k = 4) suggested significantly higher mtDNA-cn in patients compared to controls (p = 0.0275). Sub-analysis by stratifying studies based on tissue type, showed no significant increase in mtDNA-cn in blood samples among patients and controls (p = 0.284). Conversely, higher mtDNA-cn was observed in non-blood samples in patients than in controls (p = 0.0122). Further stratified analysis based on blood-cell compositions as potential confounds showed no significant difference in mtDNA-cn in peripheral blood samples of patients comparted to controls (p = 0.074). In addition, stratified analysis of aged-matched ASD and ADHD patients and controls revealed no significant difference in mtDNA-cn in blood samples between patients and controls (p = 0.214), whereas a significant increase in mtDNA-cn was observed in non-blood samples between patients and controls (p < 0.001). Finally, when the mtDNA-cn was analyzed in blood samples of aged-matched patients with ASD (peripheral blood, leukocytes, and PBMCs) or ADHD (peripheral blood), no significant difference in mtDNA-cn was observed between ASD patients and controls (p = 0.385), while a significant increase in mtDNA-cn was found between ADHD patients and controls (p = 0.033). In this first meta-analysis of the evaluation of mtDNA-cn in ASD/ADHD, our results show elevated mtDNA-cn in ASD and ADHD, further emphasizing the implication of mitochondrial dysfunction in neurodevelopmental disorders. However, our results indicate that the mtDNA-cn in blood is not reflected in other tissues in ASD/ADHD, and the true relationship between blood-derived mtDNA-cn and ASD/ADHD remains to be defined in future studies. The importance of blood-cell compositions as confounders of blood-based mtDNA-cn measurement and the advantages of salivary mtDNA-cn should be considered in future studies. Moreover, the potential of mtDNA-cn as a biomarker for mitochondrial malfunction in neurodevelopmental disorders deserves further investigations.

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.

Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH. We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes. Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported. Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.