Search Results (102)

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Fundus autofluorescence (FAF) is a non-invasive retinal imaging technique that helps visualize naturally occurring fluorophores, such as lipofuscin, and provides valuable insight into retinal diseases—particularly inherited retinal diseases (IRDs). FAF is especially useful in detecting subclinical or early-stage IRDs and in monitoring disease progression over time. In Stargardt disease, areas of decreased autofluorescence correlate with disease progression and have been proposed as a biomarker for future clinical trials. FAF can also help differentiate Stargardt disease from other macular dystrophies. In retinitis pigmentosa, hyperautofluorescent rings are a common feature on FAF and serve as an important marker for disease monitoring, especially as changes align with those seen on other imaging modalities. FAF is valuable in tracking progression of choroideremia and may help identify disease carrier status. FAF has also improved the characterization of mitochondrial retinopathies such as maternally inherited diabetes and deafness. As a rapid and widely accessible imaging modality, FAF plays a critical role in both diagnosis and longitudinal care of patients with IRDs. Full article

Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions—including dietary modulation, cofactor replacement, and gene therapy—are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer. Full article

Genetics and mitochondrial (mt) dysfunction contribute to metabolic dysfunction-associated steatotic liver disease (MASLD). Recently, we demonstrated that the co-presence of PNPLA3, TM6SF2 and MBOAT7 polymorphisms predisposes to disease progression in MASLD patients and that their deletion triggers mt maladaptation in vitro. Here, we deepened the impact of the silencing of these genes on mt dynamism and respiration by reintroducing TM6SF2 and/or MBOAT7 wild-type proteins in deleted cells through lentiviral infection. Since hepatic mt bioenergetics is impaired in MASLD, in the attempt to identify a non-invasive signature, we then compared the enzymatic mt activity of seahorses, which was assessed in liver biopsies and peripheral blood mononuclear cells (PBMCs) of biopsy-proven MASLD patients (n = 44; Discovery cohort) stratified according to the number of the three at-risk variants (3NRV). Concerning the in vitro results, the rescue of MBOAT7 and/or TM6SF2 wild-type proteins resulted in the assembly of spaghetti-shaped mitochondria with improved oxidative phosphorylation (OXPHOS) capacity. In the Discovery cohort, the hepatic bioenergetic profile fully reflected that in PBMCs and was impaired especially in 3NRV carriers. A lowered serum respiration rate was confirmed in noninvasively assessed MASLD (n = 45; Fibroscan-MASLD cohort), while it did not change in unrelated liver disease patients (n = 45). In summary, we firstly demonstrated that mt circulating respirometry reflects that in liver and is specific in defining genetic MASLD. Full article

The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (P_i) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca²⁺ uptake and buffering of matrix Ca²⁺. PiC also imports copper (Cu), crucial to COX subunit holoenzyme assembly. Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life. We have developed a novel therapeutic approach using TAT-mPiC fusion protein for cellular delivery since the TAT peptide enables delivery of proteins across biological membranes. We designed, produced, and purified the TAT-mPiC fusion protein. The fusion protein is delivered into the mitochondria and localizes within the mIM, its natural cellular location, as a processed protein. Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion. Most importantly, TAT-mPiC restored P_i and Cu delivery into the mitochondrial matrix. TAT-mPiC fusion protein also restored the mitochondrial activity of cells harboring various mitochondrial defects. This study presents the first successful delivery of a mitochondrial transmembrane carrier using the TAT-fusion system, offering a potential early treatment strategy for newborns with mPiC deficiency. 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

Background: The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the catalytic subunit of Pol-γ, can significantly impair Pol-γ enzyme function. Pol-γ-associated disorders are referred to as POLG-spectrum disorders (POLG-SDs) and are mainly autosomal-recessively inherited. Clinical manifestations include muscle weakness and fatigue, and severe forms of the disease can lead to premature death in infancy, childhood, and early adulthood, often associated with seizures, liver failure, or intractable epilepsy. Here, we analyzed fibroblasts from a compound heterozygous patient with the established pathogenic variant c.2419C>T; p.(Arg807Cys) and a previously undescribed variant c.678G>C; p.(Gln226His) with a clinical manifestation compatible with POLG-SDs, sensory ataxic neuropathy, and infantile muscular atrophy. We conducted a battery of functional studies for Pol-γ and mitochondrial dysfunction on the patient’s fibroblasts, to test whether the novel variant c.678G>C; p.(Gln226His) may be causative in human disease. Aims/Methods: We analyzed skin-derived fibroblasts in comparison to a first-degree relative (the mother of the patient), an asymptomatic carrier harboring only the established c.2419C>T; p.(Arg807Cys) mutation. Assessments of mitochondrial function included measurements of mtDNA content, mRNA levels of mitochondrial genes, mitochondrial mass, and mitochondrial morphology. Case Presentation and Results: A 13-year-old male presented with symptoms starting at three years of age, including muscle weakness and atrophy in the lower extremities and facial muscles, which later extended to the upper limbs, voice, and back muscles, without further progression. The patient also reported fatigue and muscle pain after physical activity, with no sensory deficits. Extensive diagnostic tests such as electromyography, nerve conduction studies, muscle biopsy, and MRI were unremarkable. Exome sequencing revealed that he carried the compound heterozygous variants in POLG c.678G>C; p.(Gln226His) and c.2419C>T; p.(Arg807Cys), but no other potential genetic pathogenic causes. In comparison to a first-degree relative (his mother) who only carried the c.2419C>T; p.(Arg807Cys) pathogenic mutation, in vitro analyses revealed a significant reduction in mtDNA content (~50%) and mRNA levels of mtDNA-encoded proteins. Mitochondrial mass was reduced by approximately 20%, and mitochondrial interconnectivity within cells was impaired, as determined by fluorescence microscopy and mitochondrial staining. Conclusions: Our findings suggest that the c.678G>C; p.(Gln226His) variant, in conjunction with the c.2419C>T; p.(Arg807Cys) mutation, may compromise mtDNA replication and mitochondrial function and could result in clinically significant mitochondriopathy. As this study is based on one patient compared to a first-degree relative (but with an identical mitochondrial genome), the pathogenicity of c.678G>C; p.(Gln226His) of POLG should be confirmed in future studies, in particular, in conjunction with other POLG-variants. Full article

The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases. Full article

Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disorder globally that lacks any disease-modifying drug for prevention or treatment. Oxidative stress has been identified as one of the key pathogenic drivers of Parkinson’s disease (PD). Edaravone, an approved free-radical scavenger, has proven to have potential against PD by targeting multiple key pathologies, including oxidative stress, focal mitochondria, and neuroinflammation. However, its bioavailability is potentially restricted due to its poor solubility and short half-life. This study aims to develop a simple and effective drug delivery system for edaravone to enhance its solubility, stability, and bioavailability to improve its neuroprotective efficacy. An MPEG-2000-DSPE-edaravone (MDE) micelle was prepared via solvent evaporation using MPEG-2000-DSPE as a carrier to encapsulate edaravone. The morphology, particle size, zeta potential, chemical structure, and edaravone loading of MDE were evaluated. We then investigated whether such targeted edaravone delivery could provide enhanced neuroprotection. A cell model of PD was established in PC12 cells through exposure to rotenone. The effects of MDE on PC12 cells treated with or without rotenone were evaluated using a cell counting kit-8, calcein acetoxymethyl ester (AM)–propidine iodide (PI) staining, and flow cytometry. Cell migration was evaluated using a wound healing assay. Additionally, the intracellular antioxidant study was performed using an ROS-level-detecting DCFH-DA probe, and the mitochondrial membrane potentials were evaluated using a JC-1 assay. MDE with a drug-loading content of 17.6% and an encapsulation efficiency of 92.8% was successfully prepared. The resultant MDE had a mean particle size of 112.97 ± 5.54 nm with a zeta potential of −42 mV. Cytotoxicity assays confirmed that the MDE (≤200 ug/mL) exhibited promising cytocompatibility with no significant effect on cell viability, cell cycle regulation, or apoptosis levels. Likewise, compared with the free edaravone, no effect on cell migration was noted for MDE. MDE might be able to target edaravone delivery into PC12 cells, increasing the mitochondrial membrane potential and providing a significant local antioxidant effect. The results demonstrated that MPEG-2000-DSPE could be a promising material for enhancing edaravone’s aqueous solubility, stability, and antioxidant effects. MDE could be a potential drug formulation for treating PD and other diseases in which oxidative stress plays a key role in pathogenesis. Full article

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer. Full article

Fusarium head blight in wheat is mainly caused by Fusarium graminearum and results in significant economic losses. Coenzyme Q (CoQ) is ubiquitously produced across organisms and functions as a hydrogen carrier in energy metabolism. While UbiH in Escherichia coli serves as a hydroxylase in CoQ biosynthesis, its role in phytopathogenic fungi is not well understood. This study explored the role of the hydroxylase FgUbiH in F. graminearum. Using a FgUbiH deletion mutant, we observed reduced hyphal growth, conidial production, germination, toxin synthesis, and pathogenicity compared to the wild-type. A transcriptome analysis indicated FgUbiH’s involvement in regulating carbohydrate and amino acid metabolism. Deletion of FgUbiH impaired mitochondrial function, reducing adenosine triphosphate synthesis and increasing reactive oxygen species. Additionally, genes related to terpene skeleton synthesis and aldehyde dehydrogenase were downregulated. Our results underscore the importance of FgUbiH in F. graminearum’s growth, toxin production, and energy metabolism, aiding in the development of strategies for disease management. Full article

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN. Full article

The special bilayer structure of mitochondrion is a promising therapeutic target in the diagnosis and treatment of diseases such as cancer and metabolic diseases. Nanocarriers such as liposomes modified with mitochondriotropic moieties can be developed to send therapeutic molecules to mitochondria. In this study, DSPE-PEG-TPP polymer conjugate was synthesized and used to prepare mitochondria-targeted liposomes (TPPLs) to improve the therapeutic index of chemotherapeutic agents functioning in mitochondria and reduce their side effects. Doxorubicin (Dox) loaded-TPPL and non-targeted PEGylated liposomes (PPLs) were prepared and compared based on physicochemical properties, morphology, release profile, cellular uptake, mitochondrial localization, and anticancer effects. All formulations were spherically shaped with appropriate size, dispersity, and zeta potential. The stability of the liposomes was favorable for two months at 4 °C. TPPLs localize to mitochondria, whereas PPLs do not. The empty TPPLs and PPLs were not cytotoxic to HCT116 cells. The release kinetics of Dox-loaded liposomes showed that Dox released from TPPLs was higher at pH 5.6 than at pH 7.4, which indicates a higher accumulation of the released drug in the tumor environment. The half-maximal inhibitory concentration of Dox-loaded TPPLs and PPLs was 1.62-fold and 1.17-fold lower than that of free Dox due to sustained drug release, respectively. The reactive oxygen species level was significantly increased when HCT116 cells were treated with Dox-loaded TPPLs. In conclusion, TPPLs may be promising carriers for targeted drug delivery to tumor mitochondria. Full article

Inherited retinal diseases (IRDs) are extremely heterogeneous with at least 350 causative genes, complicating the process of genetic diagnosis. We analyzed samples of 252 index cases with IRDs using the Blueprint Genetics panel for “Retinal Dystrophy” that includes 351 genes. The cause of disease could be identified in 55% of cases. A clear difference was obtained between newly recruited cases (74% solved) and cases that were previously analyzed by panels or whole exome sequencing (26% solved). As for the mode of inheritance, 75% of solved cases were autosomal recessive (AR), 10% were X-linked, 8% were autosomal dominant, and 7% were mitochondrial. Interestingly, in 12% of solved cases, structural variants (SVs) were identified as the cause of disease. The most commonly identified genes were ABCA4, EYS and USH2A, and the most common mutations were MAK-c.1297_1298ins353 and FAM161A-c.1355_1356del. In line with our previous IRD carrier analysis, we identified heterozygous AR mutations that were not the cause of disease in 36% of cases. The studied IRD panel was found to be efficient in gene identification. Some variants were misinterpreted by the pipeline, and therefore, multiple analysis tools are recommended to obtain a more accurate annotation of potential disease-causing variants. Full article