Search Results (100)

O-GlcNAcylation is a ubiquitous post-translational modification regulated by O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in response to environmental and genetic alterations. It occurs in the nucleus, mitochondrion, and cytoplasm and is implicated in cardiovascular disease (CVD) development. O-GlcNAcylation modulates diverse cellular processes, including metabolic pathways, signaling networks, and transcriptional programs. Acute increase in O-GlcNAcylation serves as an adaptive response that preserves cardiac function, whereas chronic elevation leads to persistent metabolic dysregulation and promotes pathological cardiac remodeling. In this review, we provide a comprehensive overview of the role of O-GlcNAcylation across diverse disease contexts. We also summarize the current understanding of its complex interplay with CVD, including the underlying mechanisms. Finally, we highlight existing knowledge gaps and discuss the therapeutic potential of targeting O-GlcNAcylation in various cardiovascular events, emphasizing key priorities for future research. Full article

Precise control of mitochondrial electron transport is essential to maintain mitochondrial coupling and efficiency in ATP production. Furthermore, disruptions to ETC complex function can drive increased oxidant production, resulting in oxidative damage to the mitochondrion and bioenergetic inefficiency. This is highly relevant in the aging heart, as increased cardiac oxidative stress and mitochondrial dysfunction are hallmarks of age-related cardiovascular disease. Lysine acetylation has recently been characterized as a novel regulator of mitochondrial metabolic and bioenergetic function in the aging heart. In the present study, we investigated how lysine acetylation regulates oxidant production and redox milieu through mitochondrial acetyltransferase GCN5L1. Using a cardiac-specific GCN5L1 knockout mouse model, we observed that age-associated lipid peroxidation and semiquinone radicals were decreased with GCN5L1 KO. RNA sequencing analysis identified mitochondrial bioenergetic and respiratory pathways revolving around the respiratory chain to be enriched in the old KO group. Further, we showed the old KO group to exhibit reduced acetylation of ETC complex and antioxidant proteins, improved ETC complex and antioxidant protein activity. Overall, GCN5L1 regulates redox homeostasis in the aged heart by regulating mitochondrial ETC complex activity, oxidative stress, and mitochondrial bioenergetics. These findings identify GCN5L1 and acetylation as potential therapeutic targets in aging and age-related diseases. Full article

The leishmaniases are a group of neglected tropical diseases caused by kinetoplastid protozoa of the genus Leishmania, transmitted by phlebotomine sandflies. In the absence of a human vaccine, current chemotherapeutic options remain suboptimal due to limited target selectivity, high cost, restricted availability in endemic low-resource regions, and escalating parasite resistance. This review highlights recent advances in rational drug design directed at the kinetoplast—a distinctive mitochondrial organelle critical for parasite viability. Different targets (e.g., kDNA, G-quadruplex, topoisomerases) and innovative approaches employing mitochondrion-targeted small molecules are discussed, as well as ligand-functionalized nanoparticle delivery systems that can transport bioactive agents to the parasite’s mitochondrial microenvironment. These strategies highlight the kinetoplast’s strong translational relevance as a selective antileishmanial target. By exploiting its unique molecular machinery, these strategies may offer improved parasite selectivity, although potential mitochondrial liabilities in host cells must be carefully evaluated. Full article

Background: The apicomplexan parasite Toxoplasma gondii causes serious diseases in animals and humans. The in vitro efficacy of the antimicrobial peptide mixture tyrothricin, composed of tyrocidines and gramicidins, against T. gondii tachyzoites was investigated. Methods: Effects against T. gondii were determined by monitoring inhibition of tachyzoite proliferation and electron microscopy, host cell and splenocyte toxicity was measured by Alamar blue assay, and early embryo toxicity was assessed using zebrafish embryos. Differential affinity chromatography coupled to mass spectrometry and proteomics (DAC-MS-proteomics) was employed to identify potential molecular targets in T. gondii cell-free extracts. Results: Tyrothricin inhibited T. gondii proliferation at IC₅₀s < 100 nM, with tyrocidine A being the active and gramicidin A the inactive component. Tyrothricin also impaired fibroblast, T cell and zebrafish embryo viability at 1 µM. Electron microscopy carried out after 6 h of treatment revealed cytoplasmic vacuolization and structural alterations in the parasite mitochondrion, but these changes appeared only transiently, and tachyzoites recovered after 96 h. Tyrothricin also induced a reduction in the mitochondrial membrane potential. DAC-MS-proteomics identified 521 proteins binding only to tyrocidine A. No specific binding to gramicidin A was noted, and four proteins were common to both peptides. Among the proteins binding specifically to tyrocidine A were several SRS surface antigens and secretory proteins, mitochondrial inner and outer membrane proteins associated with the electron transfer chain and porin, and several calcium-binding proteins putatively involved in signaling. Discussion: These results suggest that tyrocidine A potentially affected multiple pathways important for parasite survival and development. Full article

Chagas disease is caused by the protozoan Trypanosoma cruzi, and its current treatment is limited to the use of two nitroderivatives, benznidazole (Bz) and nifurtimox; however, their toxicity often leads to discontinuation, justifying the search for new therapeutic options. The biological activity of quinones has long shown efficacy towards pathogenic microorganisms. In our previous investigations, two naphthoquinones combining ortho- and para-quinoidal moieties exhibited remarkable trypanocidal activity and presented low toxicity to host cells. Here, these two active compounds were further assessed. On trypomastigotes and epimastigotes, brominated (NQ1) and chlorinated (NQ2) nor-beta-lapachone-derived 1,2,3-triazoles were more active than Bz, presenting IC₅₀/24 h values in the range of 0.8 to 3.1 µM. NQ1-treated epimastigotes showed a mitochondrial impairment and reactive oxygen species (ROS) production under electron microscopy and flow cytometry. The in vitro evaluation of both combinations of compounds with Bz indicated an additive interaction. In vivo, oral treatment with NQ1 reduced parasitemia in an acute model, with no evidence of toxicity. The treatment also led to a reduction in myocarditis, decreasing the PR interval in electrocardiographic analysis and reversing the sinus bradycardia caused by infection. These data suggest that T. cruzi mitochondrion are part of the NQ1 mechanism of action. In vivo, this compound presented moderate trypanocidal and promising anti-inflammatory activity. Its combination with Bz could enhance current therapeutic protocols and should be better explored in the future. Full article

The increasing threat of zoonotic malaria parasites of humans, such as Plasmodium knowlesi, make the search for improved pharmacotherapy imperative. Using protein sequence and structural analyses, phylogenetics, protein network mapping, protein–ligand interaction, and small molecule docking studies, we have identified for the first time the predicted structure, function, and druggability of the P. knowlesi heat shock protein 90s (PkHsp90s). Four isoforms were identified (in the cytosol, endoplasmic reticulum, mitochondrion, and apicoplast), and key structural differences were elucidated compared to human Hsp90s. In particular, the glycine-rich helix loop (GHL) motif of cytosolic PkHsp90 was predicted to have a straight conformation that forms a plasmodial-specific hydrophobic extension of the lid domain of the ATP-binding site, which was not observed for the cytosolic human Hsp90s, HSPC1 (Hsp90α), and HSPC3 (Hsp90β). Virtual screening identified for the first time a number of compounds from the ZINC database (ZINC22007970, ZINC724661072, and ZINC724661078) that were predicted to bind strongly to the GHL-associated pocket of PkHsp90, with weak or no binding to HSPC1. This study has provided a molecular framework in support of rational drug design, targeting PkHsp90s as a promising route for antimalarial drug development in the fight against zoonotic malaria. Full article

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, with a substantial proportion of events occurring prematurely. Atherosclerosis (AS), the central driver of cardiovascular pathology, results from the convergence of metabolic disturbances, vascular inflammation, and organelle dysfunction. Among intracellular organelles, mitochondria have emerged as critical regulators of vascular homeostasis. Beyond their canonical role in adenosine triphosphate (ATP) production, mitochondrial dysfunction—including impaired mitochondrial oxidative phosphorylation (OXPHOS), excessive generation of reactive oxygen species (ROS), accumulation of mitochondrial DNA (mtDNA) damage, dysregulated dynamics, and defective mitophagy—contributes to endothelial dysfunction, vascular smooth muscle cell (VSMC) phenotypic switching, macrophage polarization, and ultimately plaque initiation and destabilization. These insights have established the rationale for mitochondrial “reprogramming”—that is, the restoration of mitochondrial homeostasis through interventions enhancing biogenesis, dynamics, and quality control—as a novel therapeutic paradigm. Interventions that enhance mitochondrial biogenesis, restore mitophagy, and rebalance fission–fusion dynamics are showing promise in preclinical models of vascular injury. A growing array of translational strategies—including small-molecule activators such as resveratrol and Mitoquinone (MitoQ), gene-based therapies, and nanoparticle-mediated drug delivery systems—are under active investigation. This review synthesizes current mechanistic knowledge on mitochondrial dysfunction in ASand critically appraises therapeutic approaches aimed at vascular protection through mitochondrial reprogramming. Full article

Malaria remains a major global health threat, particularly in low- and middle-income countries, where children under five and pregnant women are most vulnerable. Despite notable progress in reducing malaria-related morbidity and mortality, the rise of drug-resistant Plasmodium falciparum strains continues to undermine eradication efforts. In this context, the parasite’s mitochondrion has emerged as a promising target for novel antimalarial therapies due to its essential role in parasite viability throughout all life cycle stages and its marked structural and biochemical differences from the human counterpart. This review highlights recent advances in the development of compounds targeting mitochondrial function in P. falciparum and discusses the utility of Saccharomyces cerevisiae as a powerful model organism for antimalarial drug discovery. Owing to its shared eukaryotic features, genetic tractability, and capacity for heterologous expression of parasite mitochondrial proteins, S. cerevisiae offers a cost-effective and experimentally accessible platform for elucidating drug mechanisms and accelerating therapeutic development. Full article

Fish reproduction requires suitable salinity and temperature, as well as sufficient energy. This study investigated temperature and salinity effects on ovarian development of Lateolabrax maculatus and energy metabolism differences between reproduction and growth. Two salinities (4‰ and 30‰) and temperatures (18 ± 1 °C and 30 ± 1 °C) formed four treatments: SWNT (30‰, 30 ± 1 °C), SWLT (30‰, 18 ± 1 °C), FWLT (4‰, 18 ± 1 °C), and FWNT (4‰, 30 ± 1 °C). GSI and sex hormones (FSH, LH, E2, and 17α,20β-DHP) were measured. Transcriptome analysis explored how temperature and salinity regulate ovarian development in L. maculatus, while integrated transcriptomic and targeted energy metabolomic analyses revealed energy metabolism differences between ovary and muscle during this process. The results showed that low salinity (4‰) and low temperature (18 ± 1 °C) synergistically promoted ovarian development in the FWLT group, as indicated by a significant increase in GSI and elevated levels of key sex hormones (FSH, LH, E2, and 17α,20β-DHP). Transcriptome analysis showed that low temperature activated pathways involved in steroidogenesis, oocyte maturation, and meiosis, and genes such as ADCY6, PRKACB, CPEB4, FZD7-A, and CCND2 were significantly upregulated. Salinity changes mainly affected amino acid metabolism, cholesterol metabolism, and the insulin signaling pathway. Genes such as PCSK9 and CKM may regulate ovarian development by regulating hormone synthesis and energy metabolism. Comprehensive transcriptome and metabolome analyses show that glycolysis is downregulated and oxidative phosphorylation is upregulated in the ovary, suggesting that ovarian oogenesis tends to be energized by aerobic metabolism. The TCA cycle may be used more for providing biosynthetic precursors and facilitating the transport of substrates between the mitochondrion and the cytoplasm rather than just as a source of ATP. Muscle tissue relies primarily on glycolysis for rapid energy production and may redistribute energy to the gonads, prioritizing the energy needs of the ovaries and contributing to the dynamic balance between reproduction and growth. This study provides insights into the molecular mechanisms of how environmental factors regulate fish reproduction, providing a theoretical basis and potential molecular targets for the regulation of reproduction and optimization of aquaculture environments. Full article

Paeonia ludlowii, a critically endangered species endemic to Tibet, China, possesses significant ornamental, culinary, and medicinal value. However, its mitochondrial genome remains understudied, limiting insights into its evolutionary mechanisms and constraining conservation genetics applications and molecular breeding programs. We present the first complete assembly and comprehensive analysis of the P. ludlowii mitochondrial genome. Most remarkably, we discovered that the P. ludlowii mitogenome exhibits an atypical dual-circular structure, representing the first documented occurrence of this architectural feature within the genus Paeonia. The assembled genome spans 314,371 bp and encodes 42 tRNA genes, 3 rRNA genes, and 31 protein-coding genes, with a pronounced adenine–thymine bias. This multipartite genome structure is characterized by abundant repetitive elements (112 functionally annotated SSRs, 33 tandem repeats, and 945 dispersed repeats), which potentially drive genome rearrangements and facilitate adaptive evolution. Analyses of codon usage bias and nucleotide diversity revealed highly conserved gene expression regulation with limited variability. Phylogenetic reconstruction confirms that P. ludlowii, P. suffruticosa, and P. lactiflora form a monophyletic clade, reflecting close evolutionary relationships, while extensive syntenic collinearity with other Paeonia species underscores mitochondrial genome conservation at the genus level. Extensive inter-organellar gene transfer events, particularly from chloroplast to mitochondrion, suggest that such DNA exchanges enhance genetic diversity and promote environmental adaptation. The discovery of the dual-circular architecture provides novel insights into plant mitochondrial genome evolution and structural plasticity. This study elucidates the unique structural characteristics of the P. ludlowii mitochondrial genome and establishes a crucial genetic foundation for developing targeted conservation strategies and facilitating molecular-assisted breeding programs for this endangered species. Full article

Toxoplasma gondii is an Apicomplexan parasite that possesses a well-developed system of scavengers of reactive oxygen species (ROS). Among its components, T. gondii mitochondrial superoxide dismutase (TgSOD2) is essential, as predicted by the CRISPR phenotype index and evidenced by the non-viability of its constitutive knockouts. As an obligate intracellular parasite, TgSOD2 is upregulated during extracellular stages. Herein, we generated a viable TgSOD2 knockdown mutant using an inducible auxin–degron system to explore the biological role of TgSOD2 in T. gondii. Depletion of TgSOD2 led to impaired parasite growth and replication, reduced mitochondrial membrane potential (MMP), abnormalities in the distribution of ATP synthase within its mitochondrial electron transport chain (mETC), and increased susceptibility to mETC inhibitors. Through a proximal biotinylation approach, we identified the interactions of TgSOD2 with complexes IV and V of its mETC, suggesting that these sites are sensitive to ROS. Our study provides the first insights into the role of TgSOD2 in maintaining its mitochondrial redox homeostasis and subsequent parasite replication fitness. Significance: Toxoplasma gondii infects nearly a third of the world population and can cause fetal miscarriages or life-threatening complications in vulnerable patients. Current therapies do not eradicate the parasite from the human hosts, rendering them at risk of recurrence during their lifetimes. T. gondii has a single mitochondrion, which is well-known for its susceptibility to oxidative damage that leads to T. gondii’s death. Therefore, targeting T. gondii mitochondrion remains an attractive therapeutic strategy for drug development. T. gondii’s mitochondrial superoxide dismutase is an antioxidant protein in the parasite mitochondrion and is essential for its survival. Understanding its biological role could reveal mitochondrial vulnerabilities in T. gondii and provide new leads for the development of effective treatments for T. gondii infections. Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its prevalence is expected to double in the next 30 years. Currently, no effective treatment exists for Parkinson’s disease. Thus, the research has focused on discovering new natural compounds with strong neuroprotective potential. This study aimed to investigate the effects of the methanol extract of Desmodesmus arthrodesmiformis EM13 (DaMe) on the mitochondrial damage pathway in an in vitro model of PD. The isolate of Desmodesmus arthrodesmiformis EM13 was first grown under appropriate culture conditions, and then the extract (DaMe) was prepared for use in the experiments. The total lipid and protein contents, fatty acid composition, and elemental content of DaMe were subsequently determined. Human SH-SY5Y neuroblastoma cells were pretreated with nontoxic concentrations of DaMe before 6-hydroxydopamine (6-OHDA) toxicity. Pretreatment with DaMe at concentrations of 100, 250, and 500 µg/mL showed a neuroprotective effect on 6-OHDA-induced SH-SY5Y neuroblastoma cells by decreasing the reactive oxygen species (ROS) production, decreasing the total oxidant status (TOS), increasing the total antioxidant capacity (TAC), increasing the mitochondrial membrane potential (ΔΨm), decreasing the oxidative DNA damage, and regulating gene expressions related to PD and apoptosis. Given the results of our study, we suggest that DaMe can be used as a natural source for producing drugs and dietary supplements intended to treat PD. Full article

To explore the molecular mechanism of aerobic exercise to improve heart failure and to provide a theoretical basis and experimental reference for the treatment of heart failure. Nine-week-old male mice were used to establish a left ventricular pressure overload-induced heart failure model by transverse aortic constriction (TAC). The mice were randomly divided into four groups: a sham group (SHAM), heart failure group (HF), heart failure + SKQ1 group (HS) and heart failure + aerobic exercise group (HE). The mice in the HE group were subjected to moderate-intensity aerobic exercise interventions. The mitochondrion-targeting antioxidant (SKQ1) contains the lipophilic cation TPP, which targets scavenging mitochondrial ROS. The HS group was subjected to SKQ1 (100 nmol/kg/d) interventions, which were initiated 1 week after the surgery, and the interventions lasted 8 weeks. Cardiac function was assessed by ultrasound, cardiomyocyte size by H&E and WGA staining, myocardial fibrosis by Masson’s staining, and myocardial tissue oxidative stress and apoptosis by DHE and TUNEL fluorescence staining, respectively. Western blotting was used to detect the expression of mitochondrial quality control, inflammation, and apoptosis-related proteins. In the cellular level, an in vitro cellular model was established by isolating primary cardiomyocytes from neonatal mice (2–3 days) and intervening with Ang II (1 μM) to mimic heart failure. Oxidative stress and mitochondrial membrane potential were determined in the cardiomyocytes of each group by DHE and JC-1 staining, respectively. Myocardial fibrosis was increased significantly and cardiac function was reduced significantly in the heart failure mice. Aerobic exercise and SKQ1 intervention improved cardiac function and reduced myocardial hypertrophy and myocardial fibrosis in the heart failure mice significantly. Meanwhile, aerobic exercise and SKQ1 intervention reduced the number of DHE-positive particles (p < 0.01) and inhibited myocardial oxidative stress in the heart failure mice significantly. Aerobic exercise also reduced DRP1, Parkin, and BNIP3 protein expression (p < 0.05, p < 0.01), and increased OPA1 and PINK1 protein expression (p < 0.05, p < 0.01) significantly. Moreover, aerobic exercise and SKQ1 intervention decreased the number of TUNEL-positive particles and the expression of inflammation- and apoptosis-related proteins NLRP3, TXNIP, Caspase-1, IL-1β, BAX, BAK, and p53 significantly (p < 0.05, p < 0.01). In addition, the AMPK agonist AICAR and the mitochondria-targeted ROS scavenger (SKQ1) ameliorated AngII-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in cardiomyocytes significantly. It was shown that inhibition of mitochondrial ROS by aerobic exercise, which in turn inhibits mitochondrial damage, improves mitochondrial quality control, and reduces myocardial inflammatory and apoptosis, may be an important molecular mechanism by which aerobic exercise exerts endogenous antioxidant protective effects to improve cardiac function. Full article

MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions. Full article

Gliomas are the most common primary brain tumors, representing approximately 28% of all central nervous system tumors. These tumors are characterized by rapid progression and show a median survival of approximately 18 months. The therapeutic options consist of surgical resection followed by radiotherapy and chemotherapy. Despite the multidisciplinary approach and the biomolecular role of targeted therapies, the median progression-free survival is approximately 6–8 months. The incomplete tumor compliance with treatment is due to several factors such as the presence of the blood–brain barrier, the numerous pathways involved in tumor transformation, and the presence of intra-tumoral mutations. Among these, the interaction between the mutations of genes involved in tumor bio-energetic metabolism and the functional response of the tumor has become the protagonist of numerous studies. In this scenario, the main role is played by mitochondria, cellular organelles delimited by a double membrane and containing their own DNA (mtDNA), which participates in numerous cellular processes such as the regulation of cellular metabolism, cellular proliferation, and apoptosis and is also the main source of cellular energy production. Therefore, it is understood that the mitochondrion, specifically its functional alteration, is a leading figure in tumor transformation, including brain tumors. The acquisition of mutations in the mitochondrial DNA of tumor cells and the subsequent identification of the so-called mitochondria-related genes (MRGs), both functional (mutation of Complex I) and structural (mutations of Complex III/IV), have been seen to play an important role in metabolic reprogramming with increased proliferation, resistance to apoptosis, and the progression of tumorigenesis. This demonstrates that these mitochondrial alterations could have a role not only in the intrinsic tumor biology but also in the extrinsic one associated with the therapeutic response. We aim to summarize the main mitochondrial dysfunction interactions present in gliomas and how they might impact prognosis. Full article