Search Results (495)

Mitochondrial dysfunction and oxidative stress are increasingly recognized as key contributors to the development and progression of retinal degenerative diseases, including age-related macular degeneration and inherited retinal dystrophies. Growing evidence suggests that alterations in mitochondrial function, excessive production of reactive oxygen species, defective mitophagy, and chronic inflammatory responses are closely interconnected processes that contribute to retinal cell damage and degeneration. This review provides an overview of the current understanding of the molecular mechanisms linking mitochondrial dysfunction to retinal degeneration, with particular emphasis on the impact of oxidative stress, mitochondrial quality-control pathways, and inflammatory signaling. Available evidence indicates that mitochondrial DNA damage, impaired bioenergetics, and dysregulated mitochondrial dynamics play a crucial role in the degeneration of photoreceptors and retinal pigment epithelium cells. In turn, oxidative stress further exacerbates mitochondrial impairment, creating a self-sustaining cycle that promotes disease progression. Recent advances have also highlighted the therapeutic potential of targeting mitochondrial pathways. Although several mitochondria-directed strategies have shown encouraging results in experimental models, their translation into clinical practice remains at an early stage. Overall, the available data identify mitochondria as a promising therapeutic target and support the development of precision medicine approaches aimed at preserving retinal function and slowing disease progression in patients with retinal degenerative disorders. Full article

Mitochondrial dysfunction is not merely a byproduct of transformation but a driver of tumorigenesis, metastasis, and therapeutic resistance. Recent advancements in intercellular communication have identified Extracellular Vesicles (EVs) or exosomes as critical mediators that bridge the gap between the tumor and its microenvironment (TME). These EVs contain a complex repertoire of bioactive cargo, including proteins, lipids, and RNAs. Among the class of RNAs, small non-coding RNAs, microRNAs (miRNAs), are the most abundantly expressed bioactive compounds that are selectively packaged and delivered to recipient cells. EV-delivered miRNAs can target nuclear-encoded mitochondrial genes and have also been reported to localize to mitochondria (mitomiRs), where they function as post-transcriptional regulators of bioenergetic and mitochondrial dynamic adaptations that support tumor progression. This review explores the “EV-miRNA-Mitochondria Axis”, delineating the molecular mechanisms by which EV-carried miRNAs reprogram the “Mitochondrial Information Processing System” (MIPS) - a signaling network where mitochondria integrate metabolic cues (e.g., ROS, calcium flux) to dictate critical biological outcomes, such as immune regulation and cell survival. We summarized specific sorting machineries (e.g., hnRNPA2B1, Lupus La) that package oncogenic miRNAs into EVs and how these cargoes hijack mitochondrial function upon delivery. Specifically, we discussed how EV-miRNAs induce metabolic shifts, manipulate mitochondrial dynamics (fission/fusion), and inhibit the intrinsic apoptosis to drive cancer progression. Finally, we highlighted the dual utility of these EV-miRNAs as drivers of pathogenesis and promising non-invasive biomarkers for early diagnosis, prognostic and therapeutic monitoring. Full article

Mitochondria play essential roles in cellular metabolism and signaling, regulating biosynthetic pathways, calcium homeostasis, redox balance, and cell fate beyond ATP production. Their continual remodeling through fusion, fission, and mitophagy maintains mitochondrial quality control and adapts organelle function to cellular demands. Here, we review how mitochondrial dynamics, fusion, fission, and mitophagy modulate metabolic reprogramming and signaling to drive cancer progression and therapy resistance. Emerging evidence indicates that in cancer, mitochondrial fusion enhances respiratory efficiency and oxidative phosphorylation, whereas fission promotes glycolytic adaptation, rapid biomass accumulation, and stress tolerance. Mitophagy further refines metabolic fitness by eliminating damaged mitochondria and sustaining redox homeostasis. Together, these processes underscore that dysregulation of mitochondrial dynamics is a hallmark of cancer and a key driver of metabolic reprogramming and therapeutic resistance. In this review, we summarize how mitochondrial fusion, fission, and mitophagy govern metabolic circuitry in cancer development and therapy resistance. We highlight their functional impact on tumor progression and discuss emerging therapeutic strategies targeting mitochondrial dynamics and associated machinery. Understanding this dynamic metabolic crosstalk may reveal new vulnerabilities and guide the development of mitochondria-targeted cancer therapies. Full article

Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS–STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts. Full article

Mitochondrial dysfunction is a central feature of aging, driving bioenergetic decline, increased oxidative stress, and increased vulnerability to neurodegenerative diseases. Human induced pluripotent stem cells (iPSCs) and iPSC-derived neurons provide powerful models to study these processes. Ginkgo biloba extract GBE LI1370 (GBE) has demonstrated antioxidant and mitochondria-protective properties in preclinical models, including improvements in mitochondrial membrane potential, reduction in reactive oxygen species, and enhanced neuronal survival. However, its effects on mitochondrial function in human iPSCs and their differentiated derivatives in the context of aging have not yet been investigated. This study evaluated the mitochondrial protective effects of GBE (100 µg/mL) in an established iPSC-based model of aging and in neurons and astrocytes derived from aged iPSCs. Mitochondrial parameters, including ATP production, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), superoxide levels, and mitochondrial respiration, were assessed. Aged iPSCs exhibited reduced ATP production and MMP, together with increased mtROS and superoxide levels compared to young controls. Astrocytes derived from aged iPSCs also displayed mitochondrial dysfunction. Treatment with GBE for 24 h increased ATP production and MMP, reduced oxidative stress, and improved mitochondrial respiration in both young and aged iPSCs, as well as in aged iPSC-derived neurons and astrocytes. These preliminary donor-based findings support further investigation of GBE-associated mitochondrial responses in human donor-derived cellular models of aging and warrant validation in larger donor cohorts. Full article

Background/objectives: Epithelial ovarian cancer (EOC) is the deadliest gynaecologic malignancy, largely due to late-stage diagnosis and ineffective therapy. EOC commonly spreads through the peritoneal cavity as multicellular spheroids, which are metastatic structures that enhance survival under detachment stress, promote dissemination, and contribute to therapeutic resistance. We previously showed that ULK1, a serine/threonine kinase classically linked to macroautophagy initiation, supports EOC progression, suggesting non-canonical roles in spheroid biology and pathogenesis. Methods: CRISPR/Cas9 ULK1 knockout (ULK1KO) models were generated in OVCAR8, HEYA8, and ES2 cells. Mitochondrial degradation phenotypes were assessed in spheroids by immunoblotting and fluorescence microscopy. Label-free proteomics with bioinformatic pathway analysis identified ULK1-associated programs in EOC spheroids. Bioenergetic consequences were quantified using Seahorse ATP-Rate assays. Therapeutic interactions were evaluated using multi-dose combination matrices testing the ULK1 inhibitor DCC-3116 with metformin. Results: ULK1 modulated mitochondrial degradation in a cell-line-specific manner, either promoting or protecting against mitochondrial loss through mechanisms that were uncoupled from canonical autophagy machinery. Proteomic and bioinformatic analyses revealed significant alterations in mitochondria-related processes, aligning with emerging ULK1 functions in mitochondrial homeostasis. ULK1 loss broadly reduced OXPHOS complex proteins in EOC spheroids and consistently decreased hexokinase 2 (HK2), indicating coordinated metabolic remodeling. Seahorse profiling mirrored these shifts: OVCAR8 ULK1KO spheroids showed reduced OCR and ATP production, whereas HEYA8 and ES2 ULK1KO spheroids exhibited increased mitochondrial ATP production. Combination matrices showed potential synergy between DCC-3116 and metformin. Conclusions: These data show that ULK1 differentially regulates mitochondrial degradation across EOC spheroid models through potential mechanisms alternative to canonical autophagy machinery, while reshaping spheroid metabolism and revealing potential therapeutic vulnerabilities in advanced EOC. Full article

As primary sites for oxygen consumption and energy production via oxidative phosphorylation (OXPHOS), mitochondria play a central role in the regulation of bioenergetics and generation of key metabolic intermediates for myogenic cell growth. Common methods to study mitochondria and their metabolism typically rely on population-level analyses, which can mask potential differences in individual cells. In this study, we used various imaging approaches to investigate the interplay between intracellular oxygenation, mitochondrial metabolism and dynamics in a model of myogenic differentiation. Fluorescence imaging of intracellular oxygen revealed that myogenic differentiation is accompanied by progressive shifts in intracellular oxygenation that depend upon and reflect changes in mitochondrial metabolism (i.e., higher oxygen consumption and adenosine triphosphate (ATP) production). By measuring intracellular oxygenation, we showed that mitochondrial metabolism reduces oxygen availability in the cytosol and the nucleus. Real-time redox imaging at the single-cell level further highlighted substantial metabolic heterogeneity and a shift toward OXPHOS as differentiation progressed. Morphological analyses revealed that during myogenic differentiation, mitochondria increase in size while becoming less mobile and overlapping less with microtubules. Overall, this study illustrates the value of combining complementary imaging approaches to provide a comprehensive single-cell perspective on mitochondrial metabolism, remodeling and spatial organization during myogenesis. Full article

Background: Traumatic brain injury (TBI) remains a major cause of neurological morbidity and mortality. Mitochondria, being embedded as one of the key organelles disrupted after injury, play a central role in regulating neuronal metabolism, oxidative balance, and cell survival, hence the growing interest in their role after TBI. Methods: We present a narrative review of the literature on mitochondrial dysfunction after TBI to highlight the potential role in diagnosis, monitoring, prognostication and treatment strategies. Following SANRA guidelines we conducted a synthesis of 159 selected references published between 1997 and 2026, including 70 references published from 2020 onward. Results: Mitochondrial dysfunction underpins bioenergetic failure through the impairment of critical regulatory pathways, including oxidative phosphorylation, dysregulated reactive oxygen species production, and dysregulated calcium handling. These changes trigger downstream processes of oxidative damage, epigenetic and proteomic remodeling, and activation of regulated cell death pathways such as apoptosis, necroptosis, and ferroptosis in the context of an inflammatory milieu. As such, mitochondrial-derived molecules (such as mitochondrial DNA and microRNA) are emerging candidate biomarkers of TBI severity and prognosis. Additionally, therapeutic approaches under investigation include inhibition of the mitochondrial permeability transition pore, mitigation of mitochondrial oxidative stress using targeted antioxidants, restoration of NAD⁺-dependent metabolic pathways, and metabolic support through ketogenic interventions. Conclusions: Mitochondrial biology is advancing our understanding of TBI and offers a promising framework for improving its management. Full article

Intercellular mitochondrial trafficking has emerged as an important mechanism influencing tumor progression, metabolic adaptability, and cancer cell plasticity. Beyond their classical bioenergetic functions, mitochondria act as central regulators of redox homeostasis, signaling pathways, and epigenetic remodeling. Increasing evidence suggests that mitochondria can be transferred between tumor, stromal, and immune cells through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and cell fusion within the tumor microenvironment. This dynamic excshange enables metabolically compromised cancer cells to restore oxidative phosphorylation, optimize energy production, and survive under hypoxia and therapeutic stress. Mitochondrial transfer has been increasingly associated with enhanced cellular plasticity and adaptive phenotypic transitions, including the acquisition of stem-like features that contribute to tumor heterogeneity, metastasis, and treatment resistance. In addition to bioenergetic restoration, transferred mitochondrial DNA and metabolites participate in retrograde signaling, linking metabolic state to epigenetic regulation and transcriptional reprogramming. This metabolic epigenetic interplay supports tumor cell adaptation to environmental stress and therapeutic pressure. Although significant progress has been made, the precise mechanisms governing mitochondrial integration and their long-term impact on cellular phenotypes remain incompletely understood. A deeper understanding of these processes may reveal novel therapeutic strategies to disrupt tumor adaptability and progression. Specifically, targeting intercellular mitochondrial trafficking and its associated metabolic and epigenetic effects could help limit tumor plasticity, overcome treatment resistance, reduce disease recurrence, and improve overall clinical outcomes in cancer patients. Full article

Mitochondrial stress has emerged as a key regulator of tumor–immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor–immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade. Full article

Glycolysis and the pentose phosphate pathway (PPP) are two metabolic pathways that play crucial roles in brain energy metabolism. The glycolytic pathway is differentially regulated in neurons compared to astrocytes. In neurons, the flux directly through the glycolytic pathway is reduced due to compromised ability to activate the key glycolytic enzyme 6-phosphofructo-1-kinase (PFK1). Consequently, potential increases in neuronal glucose metabolic flux can occur through the PPP, leading to the generation of NADPH, which is essential for the antioxidant defense system in these cells. Additionally, the PPP can supply glycolysis with intermediates downstream of PFK1, resulting in the production of pyruvate, which is used by mitochondria for oxidative phosphorylation and ATP production. In this review, we propose that during increased activity, neurons will preferentially metabolize glucose through the PPP. This allows them to support their antioxidant defense mechanisms and maintain bioenergetic metabolism by bypassing the limiting PFK1 enzyme and still forming pyruvate for mitochondrial oxidation. Full article

(1) Background: Calcium transfer between the endoplasmic reticulum (ER) and mitochondria through the IP3R–VDAC1 complex at mitochondria-associated ER membranes (MAMs) is essential for cellular homeostasis. Alterations in this signalling axis have been implicated in ageing and cellular senescence. (2) Methods: We developed an in vitro human dermal fibroblast (HDF) model combining replicative senescence and acute oxidative stress to investigate the role of ER–mitochondria coupling in skin ageing and to enable biomolecule screening. (3) Results: In situ proximity ligation assays revealed that replicative senescence significantly increased the number of VDAC1/IP3R complexes per cell (+85% and +72%, p < 0.01), together with elevated cellular reactive oxygen species (+47% and +74%, p < 0.05). Consistently, acute oxidative stress (50 µM t-BHP, 30 min) rapidly increased VDAC1/IP3R complexes (+48%, p < 0.001) and intra-mitochondrial calcium levels (+19%, p < 0.001). These effects persisted for 24 h post-treatment and were associated with impaired mitochondrial function (−27% in the Bioenergetic Health Index, p < 0.05). We also established a flexibility index capturing both acute and long-term adaptations and detecting the protective effects of an orchid extract. (4) Conclusions: ER–mitochondria coupling disruption via the IP3R–VDAC1 complex may contribute to oxidative stress-induced senescence and represent a key mechanism in extrinsic skin ageing. Full article

Mitochondrial RNA (mtRNA) modifications have emerged as critical regulators of pancreatic β-cell bioenergetics, influencing glucose-stimulated insulin secretion (GSIS) and the early pathogenesis of diabetes mellitus (DM). This review synthesizes current evidence on the diversity, mechanisms, and functional implications of mtRNA modifications—such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), pseudouridine (Ψ), and 5-formylcytosine (f5C)—within β-cell mitochondria. These chemical marks, installed and recognized by specific writer, eraser, and reader proteins, regulate mitochondrial translation, oxidative phosphorylation (OXPHOS) complex assembly, and redox balance. Defects in mtRNA modification machinery, exemplified by β-cell-specific knockout of TFB1M, MRM2, or PUS1, impair ribosome biogenesis, disrupt ATP production, and precipitate insulin secretory failure, as demonstrated in human islets, rodent models, and monogenic diabetes syndromes. Advances in epitranscriptomic mapping technologies—including nanopore direct RNA sequencing, RNA immunoprecipitation (RIP)-seq, and mass spectrometry—have enabled high-resolution profiling of mtRNA modification landscapes under physiological and diabetic conditions, revealing their dynamic regulation in response to metabolic stress. Furthermore, mtRNA modifications interact with environmental stressors, such as oxidative damage and toxic metals, modulating β-cell vulnerability via pathways like the mitochondrial unfolded protein response (UPRmt). Therapeutically, modulation of RNA-modifying enzymes or restoration of specific chemical marks holds promise for preserving β-cell function, with potential applications in early diagnosis, risk stratification, and precision medicine approaches for DM. Despite substantial progress, critical gaps remain in understanding the interplay between mtRNA modifications, mitochondrial-nuclear crosstalk, and β-cell plasticity. Addressing these gaps will be pivotal for translating mtRNA biology into novel biomarkers and targeted interventions for early-stage diabetes. Full article

The American Heart Association (AHA) recently formalized cardiovascular–kidney–metabolic (CKM) syndrome to characterize the systemic interplay among cardiovascular failure, chronic kidney disease (CKD), and metabolic disturbances. Despite evolving clinical management, identifying a unifying cellular driver of this multi-organ deterioration remains a critical priority. This review explores the hypothesis that mitochondrial dysfunction serves as the fundamental pathological nexus of CKM syndrome, driving the progression from early-stage metabolic risk to end-stage organ failure. We synthesize evidence demonstrating how nutrient overload and lipotoxicity precipitate a vicious cycle of bioenergetic failure. In the cardiovascular system, ATP deficiency and impaired mitophagy lead to the structural remodeling observed in both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). In the kidney, the high mitochondrial density of proximal tubules renders them uniquely susceptible to oxidative stress and mitochondrial DNA (mtDNA) leakage, which subsequently triggers systemic inflammation. Furthermore, we analyze how established therapies—including sodium–glucose co-transporter 2 (SGLT2) inhibitors, Glucagon-like peptide-1 (GLP-1) receptor agonists, and non-steroidal mineralocorticoid receptor antagonists (MRAs)—exert organ-protective effects via mitochondrial mechanisms, promoting metabolic efficiency, reducing reactive oxygen species generation, stabilizing mitochondrial integrity, and promoting mitochondrial quality control processes. Finally, we review emerging mitochondrial-targeted strategies, such as mitoquinol, elamipretide and NAD+ boosters, which aim to restore the SIRT1-PGC-1 α signaling axis. Mitochondria function as the central engines of the CKM axis. A shift toward a mitocentric clinical model may enable earlier intervention and more precise targeting of the mechanisms driving organ crosstalk. Future success depends on multidisciplinary collaboration and the validation of mitochondrial biomarkers to advance precision medicine in CKM syndrome. Full article

Mitochondrial transplantation has been proposed as a strategy to restore cellular bioenergetics after oxidative injury, but the mechanisms governing ATP recovery remain unclear. Using placental mitochondria, we examined ATP restoration following H₂O₂-induced oxidative stress. Unmodified mitochondria modestly increased ATP under baseline conditions but failed to restore ATP after injury. In contrast, lipid-coated mitochondria (MitoCoat) and lipid-encapsulated mitochondria-associated mRNAs (MitoCoat–mRNA) significantly increased ATP levels in injured cells. Transcriptomic analyses revealed that ATP recovery occurred without the normalization of canonical glycolytic or oxidative phosphorylation (OXPHOS) gene programs. Instead, unmodified mitochondria induced broad transcriptional responses associated with immune activation and cellular stress, whereas MitoCoat elicited a more restricted transcriptional profile. Notably, mitochondria-associated mRNAs alone restored ATP without detectable changes in host transcriptional programs. The removal of mitochondrial surface-associated ribosomes or the inhibition of cytosolic but not mitochondrial translation attenuated ATP recovery. The restoration of key metabolic enzymes through cytosolic translation, including PFKP, pyruvate dehydrogenase, and ATP synthase subunit ATP5A suggests that mitochondria-associated mRNAs promote recovery by re-establishing coupling between glycolysis and mitochondrial OXPHOS. Together, these findings identify encapsulated mitochondria-associated mRNAs as a potential strategy to restore cellular bioenergetics under oxidative stress. Full article