Search Results (850)

Oxidative stress, caused by an imbalance between the production of reactive oxygen species and endogenous antioxidant capacity, is a key etiological factor in numerous pathologies, including neurodegenerative and cardiovascular diseases. The limited clinical efficacy of conventional antioxidants is primarily due to their insufficient accumulation within the mitochondria, the main site of intracellular ROS generation. This article reviews the design and application of Mitochondria-Targeted Antioxidants, which represent a major advance in precision medicine. The design of these compounds involves linking an antioxidant “payload” to a lipophilic cation, such as the triphenylphosphonium group. This positive charge leverages the negative electrochemical gradient across the inner mitochondrial membrane to drive the antioxidant into the organelle. This mechanism allows the drug to reach concentrations over 100 times higher than non-targeted alternatives. The discussion encompasses the structure-activity analysis of the carrier, the payload (e.g., quinone derivatives), and the linker, which determine optimal subcellular partitioning and scavenging efficiency. Preclinical data highlight the therapeutic potential of this approach, showing strong neuroprotection in models of Parkinson’s and Alzheimer’s diseases, as well as improved outcomes in cardiovascular and ocular health. By restoring redox balance specifically within the mitochondria, these targeted therapies offer a more effective way to treat chronic oxidative damage. Full article

PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains an unresolved objective. To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Their activity was evaluated by PARP1 inhibition, cardiolipin affinity, and cytotoxicity in BRCA1-deficient HCC1937 breast cancer cells and non-malignant H9C2 cardiomyocytes. All conjugates retained potent PARP1 inhibition (IC₅₀ = 3.4–17 nM), comparable to the parent drugs. Several derivatives, particularly compounds 2d and 6c, exhibited strong cardiolipin binding (EC₅₀ = 12.99 µM and 6.77 µM, respectively) and significantly enhanced cytotoxicity in HCC1937 cells (IC₅₀ = 0.93 and 2.01 µM), outperforming olaparib and rucaparib. Notably, cytotoxicity toward H9C2 cells was lower, indicating a favorable selectivity profile. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors. Full article

Chloroplasts are key organelles in plants that carry out photosynthesis, convert light energy into chemical energy, and synthesize organic compounds. In this study, a stably heritable chlorophyll-deficient mutant was screened from the ethyl methanesulfonate-induced mutation library of Wuyunjing 21 (WYJ21). This mutant was designated as chlorophyll deficient 6 (cde6). The cde6 mutant exhibits a low chlorophyll content, photosynthetic defects, an impaired chloroplast structure, a significant reduction in the number of stacked thylakoid layers, and a yellow-green leaf phenotype in the early tillering stage. Through MutMap analysis, it was found that the cde6 mutant harbors a single-base mutation (T→A) in the LOC_Os07g38300 gene. This mutation results in an amino acid substitution from valine (Val) to aspartic acid (Asp) in the encoded protein, thereby affecting the protein’s structure and function. The mutation of CDE6 leads to decreased expression of genes related to chloroplast development and chlorophyll biosynthesis. Further studies revealed that the CDE6, a potential chloroplast ribosome recycle factor, leads to high temperature sensitivity in rice when mutated. As high-temperature stress is a primary constraint to global rice productivity, the identification of CDE6 provides a genetic target for improving thermotolerance. In conclusion, these findings demonstrate that CDE6 plays a crucial role in chloroplast biogenesis and provide new insights into its regulatory function in high-temperature tolerance. Full article

The progression of neoplastic diseases is driven by a complex interplay of biological processes, including uncontrolled proliferation, enhanced invasion, metastasis, and profound metabolic reprogramming. Among the hallmarks of cancer, as revised by Hanahan and Weinberg, the reprogramming of energy metabolism has emerged as a critical feature that enables cancer cells to meet their heightened bioenergetic and biosynthetic demands. One significant aspect of this metabolic adaptation is the accumulation of lipid droplets (LDs) dynamic, cytoplasmic organelles primarily involved in lipid storage and metabolic regulation. LDs serve as reservoirs of neutral lipids and play a multifaceted role in cancer cell physiology. Their accumulation is increasingly recognized as a marker of tumor aggressiveness and poor prognosis. By storing lipids, LDs provide a readily accessible source of energy and essential building blocks for membrane synthesis, supporting rapid cell division and growth. Moreover, LDs contribute to cellular homeostasis by modulating oxidative stress, maintaining redox balance, and regulating autophagy, particularly under nutrient-deprived or hypoxic conditions commonly found in the tumor microenvironment. Importantly, LDs have been implicated in the development of resistance to cancer therapies. They protect cancer cells from the cytotoxic effects of chemotherapeutic agents by buffering endoplasmic reticulum (ER) stress, inhibiting apoptosis, and facilitating survival pathways. The presence of LDs has been shown to correlate with increased resistance to a variety of chemotherapeutic drugs, although the precise molecular mechanisms underlying this phenomenon remain incompletely understood. Emerging evidence suggests that chemotherapy itself can induce changes in LD accumulation, further complicating treatment outcomes. Given their central role in cancer metabolism and therapy resistance, LDs represent a promising target for therapeutic intervention. Strategies aimed at disrupting lipid metabolism or inhibiting LD biogenesis have shown potential in sensitizing cancer cells to chemotherapy and overcoming drug resistance. In this review, we comprehensively examine the current understanding of LD biology in cancer, highlight studies that elucidate the link between LDs and drug resistance, and discuss emerging approaches to target lipid metabolic pathways to enhance therapeutic efficacy across diverse cancer types. Full article

Background/Objectives: Neurodegenerative diseases are driven by multiple interconnected pathological mechanisms involving both intrinsic and extrinsic molecular and cellular processes. Efficient bidirectional intracellular transport is essential for neuronal survival and function, enabling the movement of organelles, proteins, and vesicles between the neuronal soma and distal compartments. This process is primarily mediated by kinesin-dependent anterograde transport and dynein-dependent retrograde transport. Disruption of either motor protein compromises endosome–lysosome recycling, leading to cellular dysfunction and neurodegeneration. However, the mechanisms underlying motor protein impairment in Parkinson’s disease (PD) remain incompletely understood. Methods: We investigated the involvement of kinesin and dynein in intracellular transport dysfunction using both in vitro and in vivo models of PD. Cultured neuronal cells were exposed to MPP+ (1-methyl-4-phenylpyridinium) to model PD-associated neurotoxicity, and motor protein function, vesicular trafficking, and endosomal recycling were assessed. In parallel, an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD was used to evaluate dynein-positive fiber density in the spinal cord. The role of calpain-2 was examined by co-treatment with the selective calpain-2 inhibitor zLLYCH2F in both experimental systems. Results: MPP+ exposure disrupted kinesin- and dynein-mediated transport in neuronal cytoplasm, resulting in impaired vesicular trafficking and defective endosome–lysosome recycling. These alterations led to abnormal accumulation of vesicles in both perinuclear regions and at the cell periphery. Pharmacological inhibition of calpain-2 with zLLYCH2F restored motor protein function and normalized vesicle distribution in MPP+-treated cells. Consistent with in vitro findings, MPTP-treated mice exhibited a significant reduction in dynein-positive fiber density within the spinal cord, which was prevented by co-treatment with zLLYCH2F. Conclusions: Our findings demonstrate that calpain-2 activation contributes to kinesin and dynein dysfunction following MPP+/MPTP exposure, leading to impaired intracellular transport and vesicle recycling in PD models. Inhibition of calpain-2 preserves motor protein function, maintains cytoskeletal integrity, and supports normal intracellular trafficking. These results identify calpain-2 as a critical regulator of motor protein stability and suggest that targeting calpain-2 may represent a promising therapeutic strategy for mitigating intracellular transport defects in Parkinson’s disease. Full article

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity. Full article

Redox (reduction–oxidation) processes underlie all forms of life and are a universal regulatory mechanism that maintains homeostasis and adapts the organism to changes in the internal and external environments. From capturing solar energy in photosynthesis and oxygen generation to fine-tuning cellular metabolism, redox reactions are key determinants of life activity. Proteins containing sulfur- and selenium-containing amino acid residues play a crucial role in redox regulation. Their reversible oxidation by physiological oxidants, such as hydrogen peroxide (H₂O₂), plays the role of molecular switches that control enzymatic activity, protein structure, and signaling cascades. This enables rapid and flexible cellular responses to a wide range of stimuli—from growth factors and nutrient signals to toxins and stressors. Mitochondria, the main energy organelles and also the major sources of reactive oxygen species (ROS), play a special role in redox balance. On the one hand, mitochondrial ROS function as signaling molecules, regulating cellular processes, including proliferation, apoptosis, and immune response, while, on the other hand, their excessive accumulation leads to oxidative stress, damage to biomolecules, and the development of pathological processes. So, mitochondria act not only as a “generator” of redox signals but also as a central link in maintaining cellular and systemic redox homeostasis. Redox signaling forms a multi-layered cybernetic system, which includes signal perception, activation of signaling pathways, the initiation of physiological responses, and feedback regulatory mechanisms. At the molecular level, this is manifested by changes in the activity of redox-regulated proteins of which the redox proteome consists, thereby affecting the epigenetic landscape and gene expression. Physiological processes at all levels of biological organization—from subcellular to systemic—are controlled by redox mechanisms. Studying these processes opens a way to understanding the universal principles of life activity and identifying the biochemical mechanisms whose disruption causes the occurrence and development of pathological reactions. It is important to emphasize that new approaches to redox balance modulation are now actively developed, ranging from antioxidant therapy and targeted intervention on mitochondria to pharmacological and nutraceutical regulation of signaling pathways. This article analyzes the pivotal role of redox balance and its regulation at various levels of living organisms—from molecular and cellular to tissue, organ, and organismal levels—with a special emphasis on the role of mitochondria and modern strategies for influencing redox homeostasis. Full article

Stress granules (SGs) are dynamic, membraneless organelles that form in response to stress and play pivotal roles in translational control, RNA metabolism, and cell survival. In cancer, SGs are increasingly recognized as central mediators of therapy resistance, enabling malignant cells to evade apoptosis, reprogram metabolism, and modulate immune responses. Understanding the mechanistic and clinical insights into SG kinetics in healthy versus cancer cells holds significant potential for targeting them in precision oncology. This review integrates current knowledge on how chemotherapeutic agents, oncogenic signaling pathways, and tumor microenvironmental stressors promote SG formation, as well as evidence of altered SG kinetics across tumor types. We further highlight how the upregulation of SG components within the tumor microenvironment shapes cancer cell behavior and adaptability, and how crosstalk between SGs and other biomolecular condensates could contribute to resistance. Finally, we discuss emerging therapeutic strategies targeting SGs, including kinase inhibitors and modulators of SG dynamics, and propose that SGs represent tractable vulnerabilities in precision oncology. By bridging mechanistic insights with clinical implications, this review positions SGs as a promising frontier in overcoming cancer therapy resistance. Full article

Acute pancreatitis (AP) is a severe inflammatory disorder characterized by a complex molecular pathophysiology involving premature zymogen activation, organelle dysfunction, and systemic immune dysregulation. Current therapeutic strategies remain largely supportive, underscoring the critical need for specific molecular-targeted interventions. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis Georgi, has emerged as a potent pleiotropic agent. This review comprehensively synthesizes the molecular mechanisms underlying baicalein’s therapeutic efficacy in AP. Its capacity to intercept the pathological cascade at multiple checkpoints is elucidated, from mitigating the initiating cytosolic calcium overload and preserving mitochondrial integrity to suppressing the cytokine storm via the TLR4/NF-κB/MAPK signaling axis. Crucially, baicalein modulates the pancreatic immune microenvironment by driving the phenotypic polarization of macrophages from pro-inflammatory M1 to reparative M2 states and regulating neutrophil dynamics, specifically by inhibiting infiltration and neutrophil extracellular trap formation. Furthermore, its role in orchestrating regulated cell death pathways is highlighted, specifically by blocking pyroptosis and ferroptosis while modulating apoptosis, and its function as a biophysical scavenger of circulating histones and pancreatic lipase to neutralize systemic toxins. Consequently, this review emphasizes the multi-target biological activities of baicalein, providing a mechanistic rationale for its development as a precision therapeutic candidate for AP. Full article

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC—an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities. Full article

Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome–mitochondria communication. Full article

Mitochondria not only generate ATP and metabolites essential for nuclear and cytoplasmic processes but also actively shape nuclear epigenetic regulation. Conversely, the nucleus encodes most of the proteins required for mitochondrial functions, and intriguingly, certain nuclear-encoded epigenetic factors—such as DNA and histone modifiers—also localize to mitochondria, where they modulate mitochondria genome stability, gene expression, metabolic flux, and organelle integrity. This reciprocal interplay defines mitochondria as both a source and a target of epigenetic regulation, integrating energy metabolism with gene expression and cellular homeostasis. This review highlights emerging mechanisms that link mitochondrial metabolism to chromatin remodeling, DNA and histone modifications, and transcriptional control, as well as how nuclear epigenetic enzymes translocate into mitochondria and regulates their functions. We also briefly introduce recent methodological advances that enable spatially selective depletion of mitochondrial proteins, offering new tools to dissect this bidirectional communication. Together, these insights underscore mitochondria’s central role as an energetic and epigenetic hub coordinating nuclear function, development, and disease. Full article

This review summarizes recent advances (2023–2025) in coumarin-based fluorescent probes, highlighting their structural modularity, tunable VIS–NIR photophysics, and broad applicability in detecting metal ions, biothiols, ROS/RNS, organelle-specific microenvironments, and amyloid-β aggregates. Particular emphasis is placed on multifunctional and organelle-targeted probes, as well as emerging NIR-emissive and theranostic systems enabling deep-tissue imaging and modulation of pathological processes. The perspectives section outlines current limitations and future directions toward clinically relevant coumarin-based imaging tools. A though the review focuses on literature published from 2023 onward, several earlier studies are cited selectively to clarify fluorescence mechanisms, illustrate reaction pathways, or provide essential photophysical benchmarks necessary for contextual understanding. Full article

Vimentin is a type III intermediate filament protein that maintains cellular integrity, organelle positioning, and resilience to mechanical stress, but it is increasingly recognized for its dynamic change in viral infection. Viral infection causes vimentin filament disassembly into soluble oligomers with hydrophobic and acidic interfaces conducive to viral binding. These oligomers are recruited to the cell surface, where they act as viral co-receptors, facilitating viral attachment and entry. Upon entry, the viral protein induces post-translational modifications in intracellular vimentin filaments undergoing rearrangement processes, including disassembly into oligomers and then reassembly into cage-like structures that encapsulate viral replication complexes. Whether these structures promote viral replication or represent a host-imposed defense remains open. Our findings highlight the pro-viral “shield” and anti-viral “sabotage” role, a context-dependent role of vimentin during viral infection. Importantly, we offer a perspective encompassing structural biology and molecular and cellular signaling insights into vimentin dynamics, an approach that has not been explored in the current literature. We further propose that targeting vimentin is an innovative strategy for anti-viral intervention. Full article

Oil pollution effects on mangroves may be categorised as lethal (acute) and sublethal (chronic). Lethal effects usually occur at high oil dosage, which smothers and kills the entire root system and causes mass mortality. Sublethal effects occur when oil enters with tidal inundation or becomes trapped in sediments, resulting in prolonged deleterious effects that do not cause mortality. Long-term sublethal effects, however, are poorly understood. This review summarises the current information on the sublethal effects of oil pollution on mangroves. It begins by examining the characteristics of oil and then evaluates the effects of oil on propagules, roots, and leaves, as well as the underlying ecophysiological mechanisms of toxicity. Within cells, PAHs target organelles responsible for cell metabolism and energy relations, including the nucleus, mitochondria, and chloroplasts. Oil disorganises and disintegrates the lipid components of membranes, increasing their permeability. Responses of mangroves to oil include leaf senescence, defoliation and reductions in photosynthesis and biomass. Oil also decreases reproductive capacity, inhibits germination, induces mutations, and causes the development of anomalous growth forms, as well as oxidative stress and mortality. Abnormal root development at the lower portions of the stem and chlorophyll-deficient propagules are suggested as biological indicators of oil contamination in mangroves. Full article