Search Results (413)

Metabolism disorders have been seen in multiple autoimmune diseases, including SLE and Sjogren’s disease. The current studies were designed to evaluate mutations in genes involved in metabolism in a cohort of patients with Sjogren’s disease, diagnosed from clinical criteria and the presence of antibodies to salivary gland antigens. Patients were from an Immunology clinic that follows a large population of patients with autoimmune and metabolic disorders. The patients included in these studies were patients who met the criteria for Sjogren’s disease and for whom we were able to obtain genetic studies, sequencing of the mitochondrial DNA, and whole exome sequencing. There were 194 of these patients, and 192 had mutations in one or more gene involved in metabolism: 188 patients had mutations in mitochondrial respiratory chain genes, 17 patients had mutations in mitochondrial tRNA genes, 10 patients had mutations in mitochondrial DLOOP regions, 6 patients had mutations involved in carnitine transport, 6 patients had mutations in genes causing mitochondrial depletion, and 7 patients had glycogen storage diseases. In all cases, the treatment of the metabolic disorder led to symptomatic improvement in energy, exercise tolerance, gastrointestinal dysmotility, and the management of infections. In conclusion, metabolic disorders are common in patients with Sjogren’s disease and may be one of the factors leading to the initiation of the disease. The treatment of patients with Sjogren’s disease should include the treatment of the underlying/associated metabolic disorder. Full article

The m.13513G>A (p.Asp393Asn) substitution in the MT-ND5 (Mitochondrially Encoded NADH/Ubiquinone Oxidoreductase Core Subunit 5) gene is a common pathogenic variant associated with primary mitochondrial disorders. It frequently causes Leigh syndrome and mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). In this study, we present clinical data, heteroplasmy levels in various tissues (blood, urine, and skin fibroblasts), and bioenergetic characteristics from a cohort of 20 unrelated patients carrying the m.13513G>A mutation, classified according to the following phenotypes: Leigh syndrome (n = 12), MELAS (n = 2), and Leber’s hereditary optic neuropathy (LHON, n = 6). We observed a significant correlation between high respiratory ratios and heteroplasmy levels in fibroblast cell lines of the patients. Furthermore, fibroblast cell lines with heteroplasmy levels exceeding 55% exhibited markedly reduced mitochondrial membrane potential. These findings contribute to a better understanding of the clinical and bioenergetic profiles of patients with m.13513G>A-variant-related phenotypes across different heteroplasmy levels, based on data from a single genetic center. Our data suggest that even a slight shift in heteroplasmy can improve cellular function and, consequently, the patients’ phenotype, providing a solid foundation for the development of future gene therapies for mtDNA diseases. Full article

Azelaic acid (AZA), an aliphatic dicarboxylic acid (HOOC-(CH2)₇-COOH), is widely used in dermatology. It functions as an inhibitor of tyrosinase, mitochondrial respiratory chain enzymes, and DNA synthesis, while also scavenging free radicals and reducing reactive oxygen species (ROS) production by neutrophils. AZA has demonstrated anti-proliferative and cytotoxic effects on various cancer cells. However, its therapeutic potential in acute myeloid leukemia (AML) remains largely unexplored. AML is a complex hematologic malignancy characterized by the clonal transformation of hematopoietic precursor cells, involving chromosomal rearrangements and multiple gene mutations. The disease is associated with poor prognosis and high relapse rates, primarily due to its propensity to develop resistance to treatment. Recent studies indicate that AZA suppresses AML cell proliferation by inducing apoptosis and arresting the cell cycle at the G1 phase, with minimal cytotoxic effects on healthy cells. Additionally, AZA exerts antileukemic activity by modulating the ROS signaling pathway, enhancing the total antioxidant capacity in both AML cell lines and patient-derived cells. AZA also sensitizes AML cells to Ara-C chemotherapy. In vivo, AZA has been shown to reduce leukemic spleen infiltration and extend survival. As our understanding of AML biology progresses, the development of new molecularly targeted agents, in combination with traditional chemotherapy, offers the potential for improved treatment outcomes. This review aims to provide a comprehensive synthesis of preclinical evidence on the therapeutic potential of AZA in AML, consolidating current knowledge and identifying future directions for its clinical application. Full article

Background: Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and fatal neurodegenerative disease that affects the muscles and results in paralysis. The onset and development of ALS involve complex interactions among metabolic signaling, genetic pathways, and external factors (epigenetics). New biomarkers and alternative therapeutic targets have been suggested; nonetheless, the results have been unsatisfactory. Mutations in SOD1, fused in sarcoma (FUS), and TAR DNA-binding protein 43 (TDP-43) have been identified in sporadic amyotrophic lateral sclerosis and approximately 12–20% of familial amyotrophic lateral sclerosis (fALS). Aim: This review analyzes dysregulated microRNA signaling pathways and their interactions with metabolic pathways in the context of ALS progression. Significance: Despite this, biomarkers remain unreliable, and the current medications prolong life without providing a cure. Some proposed approaches to control ALS progression include balancing autophagy and apoptosis, eliminating aggregated proteins, addressing mitochondrial dysfunction, and reducing inflammation. There is a need for studies on new biomarkers, medications, and therapeutic targets. In this context, deregulated circulating microRNAs are attracting attention for new studies on ALS at various phases of the disease. Despite the extensive literature on microRNAs as potential biomarkers for ALS, the proposition for translational clinical use remains limited. Studies have indicated a significant downregulation or upregulation of microRNAs in the motor neurons of ALS patients compared with those with other neurodegenerative disorders and healthy controls. The microRNA biogenesis highlights the importance of this study. MicroRNAs regulate protein synthesis (translation); all human cells express many microRNAs. The complementary structures of microRNA sequences and their mRNA targets allow them to significantly alter cellular and physiological processes. Studies have examined these microRNAs as potential biomarkers for several physiological states and diseases. Comments: The success of these studies may lead to simple, low-cost, and efficient solutions for controlling the progression of ALS and other degenerative diseases. As a result, it is challenging to identify a specific biomarker with total reliability, as a specific microRNA that is increased in one disease phase can decrease in another. These points require careful consideration. They exhibit several complexities and varied interactions, focusing on mRNA targets. The current critical review highlights the potential of microRNAs as biomarkers for diagnosis, prognosis, and therapeutic options in ALS, and raises several points for discussion. Conclusions: The current critical review highlights the potential of microRNAs as biomarkers for diagnosis, prognosis, and therapeutic options in ALS, and raises several points for discussion. Full article

The pale grass blue butterfly Zizeeria maha has been used to evaluate the biological effects of the Fukushima nuclear accident in 2011. Here, we examined the DNA sequences of the mitochondrial gene cytochrome oxidase subunit I (COI) of Z. maha using the field samples collected in 2011–2014 and 2021. Among 641 individuals from 44 localities in Northeastern Japan, we detected a heteroplasmic nonsynonymous nucleotide substitution in one out of three 2012 individuals from Hirono, Fukushima Prefecture, where the biological impact of radioactive pollution was the highest among the localities surveyed in 2012, suggesting DNA damage via initial exposure to short-lived radionuclides. An additional 80 individuals from Hirono in 2021 did not show any substitution, suggesting the extinction of the Hirono mutant by 2021. We also detected another heteroplasmic and homoplasmic nonsynonymous substitution in four out of five 2014 individuals from Shibata, Niigata Prefecture, where radioactive pollution was low. These substitutions were not present in the GenBank records of Z. maha and its sister species Z. karsandra, indicating that intraspecific variation may exceed interspecific variation in Z. maha. These results highlight not only the possible impact of the initial exposure in Fukushima but also real-time molecular evolution of butterflies in the field. Full article

Mitochondria are indispensable in cells and play crucial roles in maintaining cellular homeostasis, energy production, and regulating cell death. Mitochondrial dysfunction has various manifestations, causing different diseases by affecting the diverse functions of mitochondria in the body. Previous studies have mainly focused on mitochondrial-related diseases caused by nuclear gene mutations or mitochondrial gene mutations, or mitochondrial dysfunction resulting from epigenetic regulation, such as DNA and histone modification. In recent years, as a popular research area, m⁶A has been involved in a variety of important processes under physiological and pathological conditions. However, there are few summaries on how RNA methylation, especially m⁶A RNA methylation, affects mitochondrial function. Additionally, the role of m⁶A in pathology through influencing mitochondrial function may provide us with a new perspective on disease treatment. In this review, we summarize several manifestations of mitochondrial dysfunction and compile examples from recent years of how m⁶A affects mitochondrial function and its role in some diseases. Full article

Background/Objectives: TDP-43 mutation-driven Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is one of the most prominent forms (approximately 97%) in cases of sporadic ALS. Dysfunctional autophagy and lysosomal function are the prime mechanisms behind ALS. Mitoxantrone (Mito), a synthetic doxorubicin analog, is an inhibitor of DNA and RNA synthesis/repair via intercalating with nitrogenous bases and inhibiting topoisomerase II. The therapeutic potential of miRNAs associated with disease conditions has also been reported. This study explores the therapeutic potential of Mito along with miRNAs against mutated TDP-43 protein-induced proteinopathy in human-induced pluripotent stem cell (hiPSC)-derived human neural progenitor cells (hNPCs). Methods: HiPSCs mutated for TDP-43 were differentiated into hNPCs and used to explore the therapeutic potential of Mito at a concentration of 1 μM for 24 h (the identified non-cytotoxic dose). The therapeutic effects of Mito on miRNA expression and various cellular parameters such as mitochondrial dynamics, autophagy, and stress granules were assessed using the high-throughput Open Array technique, immunocytochemistry, flow cytometry, immunoblotting, and mitochondrial bioenergetic assay. Results: Mutated TDP-43 protein accumulation causes stress granule formation (G3BP1), mitochondrial bioenergetic dysfunction, SOD1 accumulation, hyperactivated autophagy, and ER stress in hNPCs. The mutated hNPCs also show dysregulation in six miRNAs (miR-543, miR-34a, miR-200c, miR-22, miR-29b, and miR-29c) in mutated hNPCs. A significant restoration of TDP-43 mutation-induced alterations could be witnessed upon the exposure of mutated hNPCs to Mito. Conclusions: Our study indicates that miR-543, miR-29b, miR-22, miR-200c, and miR-34a have antisense therapeutic potential alone and in combination with Mitoxantrone. Full article

Impaired function of Polymerase-γ (Pol-γ) results in impaired replication of the mitochondrial genome (mtDNA). Pathogenic mutations in the POLG gene cause dysfunctional Pol-γ and dysfunctional mitochondria and are associated with a spectrum of neurogenetic disorders referred to as POLG spectrum disorders (POLG-SDs), which are characterized by neurologic dysfunction and premature death. Pathomechanistic studies and human cell models of these diseases are scarce. SH-SY5Y cells (SHC) are an easy-to-handle and low-cost human-derived neuronal cell model commonly used in neuroscientific research. Here, we aimed to study the effect of reduced Pol-γ function using stable lentivirus-based shRNA-mediated knockdown of POLG in SHC, in both the proliferating cells and SHC-derived neurons. POLG knockdown resulted in approximately 50% reductions in POLG mRNA and protein levels in naïve SHC, mimicking the residual Pol-γ activity observed in patients with common pathogenic POLG mutations. Knockdown cells exhibited decreased mtDNA content, reduced levels of mitochondrial-encoded proteins, and altered mitochondrial morphology and distribution. Notably, while chemical induction of mtDNA depletion via ddC could be rescued by the mitochondrial biosynthesis stimulators AICAR, cilostazol and resveratrol (but not MitoQ and formoterol) in control cells, POLG-knockdown cells were resistant to mitochondrial biosynthesis-mediated induction of mtDNA increase, highlighting the specificity of the model, and pathomechanistically hinting towards inefficiency of mitochondrial stimulation without sufficient Pol-γ activity. In differentiated SHC-derived human neurons, POLG-knockdown cells showed impaired neuronal differentiation capacity, disrupted cytoskeletal organization, and abnormal perinuclear clustering of mitochondria. In sum, our model not only recapitulates key features of POLG-SDs such as impaired mtDNA content, which cannot be rescued by mitochondrial biosynthesis stimulation, but also reduced ATP production, perinuclear clustering of mitochondria and impaired neuronal differentiation. It also offers a simple, cost-effective and human (and, as such, disease-relevant) platform for investigating disease mechanisms, one with screening potential for therapeutic approaches for POLG-related mitochondrial dysfunction in human neurons. Full article

The heart requires a continuous energy supply to sustain its unceasing contraction–relaxation cycle. Mitochondria, a double-membrane organelle, generate approximately 90% of cellular energy as adenosine triphosphate (ATP) through oxidative phosphorylation, utilizing the electrochemical gradient established by the respiratory chain. Mitochondrial function is compromised by damage to mitochondrial DNA, including point mutations, deletions, duplications, or inversions. Additionally, disruptions to proteins associated with mitochondrial membranes regulating metabolic homeostasis can impair the respiratory chain’s efficiency. This results in diminished ATP production and increased generation of reactive oxygen species. This review provides an overview of mutations affecting mitochondrial transporters and proteins involved in mitochondrial energy synthesis, particularly those involved in ATP synthesis and mobilization, and it examines their role in the pathogenesis of specific cardiomyopathies. Full article

Mitochondria are vital organelles responsible for ATP production and metabolic regulation, essential for energy-intensive cells such as retinal ganglion cells. Dysfunction in mitochondrial oxidative phosphorylation or mitochondrial DNA (mtDNA) pathogenic variants can disrupt ATP synthesis, cause oxidative stress, and lead to cell death. This has profound implications for tissues such as the retina, optic nerve, and retinal pigment epithelium, which are dependent on robust mitochondrial function. In this review, we provide a comprehensive compilation of pathogenic variants in the mtDNA associated with various ophthalmic diseases, including Leber’s hereditary optic neuropathy, chronic progressive external ophthalmoplegia, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, among others. We highlight the genetic variants implicated in these conditions, their pathogenic roles, and the phenotypic consequences of mitochondrial dysfunction in ocular tissues. In addition to well-established mutations, we also discuss the emerging evidence of the role of mtDNA’s variants in complex multifactorial diseases, such as non-arteritic anterior ischemic optic neuropathy, primary open-angle glaucoma, and age-related macular degeneration. The review aims to serve as a valuable resource for clinicians and researchers, providing a detailed overview of mtDNA pathogenic variants and their clinical significance in the context of mitochondrial-related eye diseases. Full article

Neurodegenerative diseases are a group of diseases that share common features, such as the generation of misfolded protein deposits and increased oxidative stress. Among them, amyotrophic lateral sclerosis (ALS), whose pathogenesis is still not entirely clear, is a complex neurodegenerative disease linked both to gene mutations affecting different proteins, such as superoxide dismutase 1, Tar DNA binding protein 43, Chromosome 9 open frame 72, and Fused in Sarcoma, and to altered iron homeostasis, mitochondrial dysfunction, oxidative stress, and impaired glutamate metabolism. The purpose of this review is to highlight the molecular targets common to ALS and ferroptosis. Indeed, many pathways implicated in the disease are hallmarks of ferroptosis, a recently discovered type of iron-dependent programmed cell death characterized by increased reactive oxygen species (ROS) and lipid peroxidation. Iron accumulation results in mitochondrial dysfunction and increased levels of ROS, lipid peroxidation, and ferroptosis triggers; in addition, the inhibition of the Xc⁻ system results in reduced cystine levels and glutamate accumulation, leading to excitotoxicity and the inhibition of GPx4 synthesis. These results highlight the potential involvement of ferroptosis in ALS, providing new molecular and biochemical targets that could be exploited in the treatment of the disease using polyphenols. Full article

The mechanisms of pathogenesis of hypertrophic cardiomyopathy are associated with mutations in the sarcomere genes of cardiomyocytes and metabolic disorders of the cell, including mitochondrial dysfunction. Mitochondria are characterized by the presence of their own DNA and enzyme complexes involved in oxidative reactions, which cause damage to mitochondrial protein structures and membranes by reactive oxygen species. Mitochondrial dysfunctions can also be associated with mutations in the genes encoding mitochondrial proteins and lead to a violation of protective functions such as mitophagy, mitochondrial fusion, and fission. Mutations in myofibril proteins can negatively affect mitochondria through increased oxidative stress due to an increased need for ATP. Mitochondrial dysfunction is associated with impaired ATP synthesis and cardiac contractility, leading to clinical manifestations of hypertrophic cardiomyopathy. The current review was designed to characterize the role of mitochondria in the pathogenesis of hypertrophic cardiomyopathy based on published data; the search for publications was based on the analysis of articles including the keywords “hypertrophic cardiomyopathy, mitochondria, dysfunction” in the PubMed and Scopus databases up to January 2025. Full article

Mitochondrial dysfunction is increasingly recognized as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Mitochondria, known as the powerhouses of the cell, play a vital role in maintaining cardiac energy homeostasis, regulating reactive oxygen species (ROS) production and controlling cell death pathways. Dysregulated mitochondrial function results in impaired adenosine triphosphate (ATP) production, excessive ROS generation, and activation of apoptotic and necrotic pathways, collectively driving the progression of CVDs. This review provides a detailed examination of the molecular mechanisms underlying mitochondrial dysfunction in CVDs, including mutations in mitochondrial DNA (mtDNA), defects in oxidative phosphorylation (OXPHOS), and alterations in mitochondrial dynamics (fusion, fission, and mitophagy). Additionally, the role of mitochondrial dysfunction in specific cardiovascular conditions is explored, highlighting its impact on endothelial dysfunction, myocardial remodeling, and arrhythmias. Emerging therapeutic strategies targeting mitochondrial dysfunction, such as mitochondrial antioxidants, metabolic modulators, and gene therapy, are also discussed. By synthesizing recent advances in mitochondrial biology and cardiovascular research, this review aims to enhance understanding of the role of mitochondria in CVDs and identify potential therapeutic targets to improve cardiovascular outcomes. Full article

Hypermobile Ehlers–Danlos Syndrome (hEDS) is a hereditary connective tissue disorder characterized by joint hypermobility, skin hyperextensibility, and systemic manifestations such as chronic fatigue, gastrointestinal dysfunction, and neurological symptoms. Unlike other EDS subtypes with known genetic mutations, hEDS lacks definitive markers, suggesting a multifactorial etiology involving both mitochondrial dysfunction and non-mitochondrial pathways. This scoping review, conducted in accordance with the PRISMA-ScR guidelines, highlights mitochondrial dysfunction as a potential unifying mechanism in hEDS pathophysiology. Impaired oxidative phosphorylation (OXPHOS), elevated reactive oxygen species (ROS) levels, and calcium dysregulation disrupt cellular energetics and extracellular matrix (ECM) homeostasis, contributing to the hallmark features of hEDS. We reviewed candidate genes associated with ECM remodeling, signaling pathways, and immune regulation. Protein–protein interaction (PPI) network analyses revealed interconnected pathways linking mitochondrial dysfunction with these candidate genes. Comparative insights from Fabry disease and fragile X premutation carriers underscore shared mechanisms such as RNA toxicity, matrix metalloproteinases (MMP) activation, and ECM degradation. These findings may suggest that mitochondrial dysfunction amplifies systemic manifestations through its interplay with non-mitochondrial molecular pathways. By integrating these perspectives, this review provides a potential framework for understanding hEDS pathogenesis while highlighting latent avenues for future research into its molecular basis. Understanding the potential role of mitochondrial dysfunction in hEDS not only sheds light on its complex molecular etiology but also opens new paths for targeted interventions. Full article

Mitochondrial diseases are complex disorders caused by nuclear or mitochondrial DNA mutations, leading to oxidative phosphorylation deficiency and excessive production of reactive oxygen species (ROS). While ROS have been well established in the pathogenesis of these diseases, the role of reactive nitrogen species (RNS) remains unclear. In this study, we performed a quantitative analysis of muscle fibers to investigate the relationship between protein nitration and mitochondrial abnormalities (mitochondrial proliferation and cytochrome-c oxidase (COX) deficiency) and factors like genotype, muscle damage, and age. A total of 1961 muscle fibers (303 from 4 controls and 1658 from 29 patients with mitochondrial diseases) were analyzed by immunostaining for nitro-tyrosine. Contrary to previous findings, which identified nitro-tyrosine only in small muscle vessels, we observed a broader distribution affecting the sarcolemma and sarcoplasm. Using multivariate techniques, we identified a significant correlation between protein nitration and mitochondrial proliferation but found no associations with COX deficiency, age, muscle damage, or genotype. These findings suggest that nitrative stress may contribute to mitochondrial dysfunction or play a role in signaling processes that induce mitochondrial biogenesis. Our results provide new insights into the molecular mechanisms of mitochondrial diseases and highlight the potential relevance of protein nitration. Full article