Search Results (458)

Background/Objectives: We have previously demonstrated that fatty acid oxidation (FAO) enzymes physically and functionally interact with electron transfer chain supercomplexes (ETC-SC) at two contact points. The FAO trifunctional protein (TFP) and electron transfer flavoprotein dehydrogenase (ETFDH) interact with the NADH⁺-binding domain of ETC complex I (com I) and the core 2 subunit of complex III (com III), respectively. In addition, the FAO enzyme very-long-chain acyl-CoA dehydrogenase (VLCAD) interacts with TFP. These interactions define a functional FAO-ETC macromolecular complex (FAO-ETC MEC) in which FAO-generated NADH⁺ and FADH₂ can safely transfer electron equivalents to ETC in order to generate ATP. Methods: In this study, we use multiple mitochondrial functional studies to demonstrate the effect of added VLCAD protein on mutant mitochondria. Results: We demonstrate that heart mitochondria from a VLCAD knockout (KO) mouse exhibit disrupted supercomplexes, with significantly reduced levels of TFPα and TFPβ subunits, electron transfer flavoprotein a-subunit (ETFα), and NDUFV2 subunit of com I in the FAO-ETC MEC. In addition, the activities of individual oxidative phosphorylation (OXPHOS) enzymes are decreased, as is the transfer of reducing equivalents from palmitoyl-CoA to ETC (FAO-ETC flux). However, the total amount of these proteins did not decrease in VLCAD KO animals. These results suggest that loss of VLCAD affects the interactions of FAO and ETC proteins in the FAO-ETC MEC. Reconstitution of VLCAD-deficient heart mitochondria with recombinant VLCAD improved the levels of FAO-ETC MEC proteins and enzyme activities, as well as restoring FAO-ETC flux. It also reduced mitochondrial ROS levels, previously demonstrated to be elevated in VLCAD-deficient mitochondria. In contrast, incubation of VLCAD KO mitochondria with two VLCADs with mutations in the C-terminal domain of the enzyme (A450P and L462P) did not restore FAO-ETC MECs. Conclusions: These results suggest that VLCAD is a necessary component of the FAO-ETC MEC and plays a major role in assembly of the macro-supercomplex. These studies provide evidence that both the level of enzyme and its structural confirmation are necessary to stabilize the FAO-ETC MEC. Full article

Myeloid malignancies exhibit profound metabolic dependence on mitochondrial oxidative phosphorylation (OXPHOS) for survival and proliferation. Antileukemic therapies such as Venetoclax combined with Azacitidine or cytarabine induce rapid mitochondrial collapse, disrupting electron transport, NADH oxidation, and ATP synthesis, followed by a selective rebound of fatty-acid oxidation (FAO) and redox-buffering programs that sustain minimal residual disease. This review integrates current mechanistic and clinical insights into therapy-induced mitochondrial suppression, delineates the regulatory circuitry that enables metabolic recovery, and frames these events as a reversible model of clinical energy deficiency. By linking mitochondrial stress signaling, lipid oxidation, and adaptive redox metabolism, we outline how bioenergetic reprogramming drives therapeutic resistance and propose interventions that target this adaptive axis in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and related myeloid neoplasms. Full article

Background: Triple-negative breast cancer (TNBC) is more likely to metastasise to the lungs than other breast cancer (BrCa) types, yet the molecular interactions within the tumour microenvironment (TME) at secondary sites remain poorly understood. Methods: This pilot study aimed to explore the metabolic crosstalk between MDA-MB-231 TNBC cells and MRC-5 lung fibroblasts within a co-culture system to replicate the lung metastatic TME. Co-cultures were also treated with Vitamin D or Vitamin E to evaluate the effects of these nutraceuticals on the metabolic crosstalk between TNBC cells and fibroblasts. Results: Our findings demonstrate that co-culture induced the activation of fibroblasts into cancer-associated fibroblasts (CAFs), evidenced by increased α-SMA and FAP expression. Metabolic profiling revealed that TNBC cells in co-culture displayed increased expression of enzymes associated with oxidative phosphorylation (OXPHOS) and glutamine metabolism, while fibroblasts exhibited a metabolic profile consistent with glycolysis and lactate metabolism. Vitamin D inhibited lactate metabolism and HIF-1α expression in fibroblasts while suppressing TCA cycle activity in cancer cells, suggesting a potential role in disrupting oncogenic metabolic crosstalk. Conversely, Vitamin E treatment was associated with increased expression of TCA cycle and oxidative metabolism-related markers in BrCa cells without significantly affecting fibroblast glycolysis. Such differential metabolic responses may contribute to metabolic heterogeneity within the tumour microenvironment. Conclusions: These results provide valuable insights into the metabolic dynamics of TNBC metastases in the lung TME and demonstrate that Vitamins D and E exert distinct effects on metabolic crosstalk between cancer cells and fibroblasts. These findings may have significant implications for the potential supplementation of Vitamins D and E in patients with metastatic TNBC and justify further in-depth analysis. Full article

Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP production by OXPHOS generates reactive oxygen species (ROS) that pose a significant threat to the nearby mtDNA. To counter these insults, neurons rely on base excision repair (BER), the principal mechanism for removing oxidative and other small, non-bulky base lesions in nuclear and mtDNA. BER involves a coordinated enzymatic pathway that excises damaged bases and restores DNA integrity, helping maintain mitochondrial genome stability, which is vital for neuronal bioenergetics and survival. When mitochondrial BER is impaired, mtDNA becomes unstable, leading to ETC dysfunction and a self-perpetuating cycle of bioenergetic failure, elevated ROS levels, and continued mtDNA damage. Damaged mtDNA fragments can escape into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways and inflammasome complexes. Chronic activation of these pathways drives sustained neuroinflammation, exacerbating mitochondrial dysfunction and neuronal loss, and functionally links genome instability to innate immune signaling in neurodegenerative diseases. This review summarizes recent advancements in understanding how BER preserves mitochondrial genome stability, affects neuronal health when dysfunctional, and contributes to damage-driven neuroinflammation and neurodegenerative disease progression. We also explore emerging therapeutic strategies to enhance mtDNA repair, optimize its mitochondrial environment, and modulate neuroimmune pathways to counteract neurodegeneration. Full article

Estrogen (E2, 17β estradiol) is recognized for its regulatory role in numerous genes associated with energy metabolism and for its ability to disrupt mitochondrial function in various cancer types. However, the influence of E2 on the metabolism of colorectal cancer (CRC) cells remains largely unexplored. In this study, we examined how E2 affects mitochondrial function and energy production in CRC cells, utilizing two distinct CRC cell lines, HCT-116 and SW480. Cell viability, mitochondrial function, and the expression of several genes involved in oxidative phosphorylation (OXPHOS) were assessed in estrogen receptor α (ERα)-expressing and ERα-silenced cells treated with increasing concentrations of E2 for 48 h. Our results indicated that the cytotoxicity of E2 against CRC cells is mediated by the E2/ERα complex, which induces disturbances in mitochondrial function and the OXPHOS pathway. Furthermore, we identified two novel targets, RPS2 and TMEM177, which displayed overexpression, hypomethylation, and a negative association with ERα expression in CRC tissue. E2 treatment in CRC cells reduced the expression of both targets through promoter hypermethylation. Treatment with 5-Aza-2-deoxycytidine increased the expression of RPS2 and TMEM177. This epigenetic effect disrupts the mitochondrial membrane potential (MMP), resulting in decreased activity of the OXPHOS pathway and inhibition of CRC cell growth. Knockdown of RPS2 or TMEM177 in CRC cells resulted in anti-cancer effects and disruption of MMP and OXPHOS. These findings suggest that E2 exerts ERα-dependent epigenetic reprogramming that leads to significant mitochondria-related anti-growth effects in CRC. 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

Mitochondrial oxidative phosphorylation serves as a critical driving force in the progression of ovarian cancer. Recent studies have demonstrated that copper induces mitochondrial-dependent programmed cell death by directly binding to the thioacylated components of the tricarboxylic acid (TCA) cycle. The involvement of copper in OXPHOS complex IV, a rate-limiting step in the mitochondrial respiratory chain, suggests that the role of mitochondria in mediating copper-induced cell death can be further elucidated through the study of OXPHOS complex IV. The findings of this study indicate that the cuproptosis process in ovarian cancer, induced by Elesclomol, is associated with mitochondrial complex IV, with LRPPRC identified as a crucial factor. Following Elesclomol treatment of ovarian cancer cells, there was a notable increase in mitochondrial reactive oxygen species (ROS), a significant accumulation of the copper death marker protein DLAT, and a marked decrease in the lipoic acid synthesis-related protein FDX1. Furthermore, the expression levels of copper ion transporters ATP7B and CTR1, which are involved in the assembly and translation of complex IV, as well as the core subunit MTCO1 of complex IV, the copper chaperone protein SCO1, and the interacting protein LRPPRC, were significantly diminished. Inhibition of the IV-stabilizing protein LRPPRC in the ovarian cancer cell lines A2780 and SKOV3 through RNA interference resulted in increased sensitivity to Elesclomol. Concurrently, the expression levels of FDX1, LIAS, LIPT1, SCO1, and MTCO1 decreased significantly. These findings suggest that LRPPRC plays a role in inhibiting the expression of lipoic acid and copper chaperone proteins during Elesclomol-induced copper death in ovarian cancer. This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer. Full article

Drug repositioning, also known as drug repurposing, represents a cost-effective and time-efficient approach to accelerate the development of novel therapies for colorectal cancer (CRC), the third most common cancer worldwide, with an estimated two million new cases and nearly one million deaths annually. This review aims to critically evaluate how existing non-oncologic drugs can be repositioned to exploit key metabolic vulnerabilities of CRC cells. Targeting cancer cell metabolism offers a unique therapeutic advantage, as it disrupts the bioenergetic and biosynthetic processes that sustain tumor growth, adaptation, and resistance to therapy. Specifically, we examine the mechanisms through which antidiabetic, cardiovascular, anti-inflammatory, antidepressant, and anthelmintic agents interfere with glycolysis, oxidative phosphorylation (OxPhos), and mitochondrial bioenergetics—metabolic circuits central to CRC progression and recurrence. By integrating recent mechanistic, preclinical, and clinical findings, we highlight how these repurposed drugs converge on major metabolic regulators, including the AMPK/mTOR signaling pathways, and how they can potentiate the efficacy of standard chemotherapies and immunotherapies. Furthermore, we discuss the translational challenges that must be addressed to move these compounds into clinical use. Collectively, this review underscores the therapeutic potential of targeting CRC metabolism through drug repositioning as a promising avenue toward more effective and personalized treatment strategies. Full article

Ever since the discovery that neuronal tissue can utilize lactate as an aerobic substrate for mitochondrial adenosine triphosphate (ATP) production, a debate has ensued between those who have questioned the importance of lactate in brain energy metabolism and those who argue that lactate plays a central role in this process. The “neuron astrocyte lactate shuttle hypothesis” has sharpened this debate since it postulates lactate to be the oxidative energy substrate for activated neurons. Those who minimize lactate’s role insist that a non-oxidative process they termed “aerobic glycolysis” supports brain activation, despite oxygen availability. To explain the paradox that the active brain would utilize the inefficient glycolysis over the much more efficient mitochondrial oxidative phosphorylation (OXPHOS) for ATP production, they suggested the “efficiency tradeoff hypothesis,” where the inefficiency of the glycolytic pathway is traded for speed necessary for the information transfer of the active brain. In contrast, other studies reveal that oxidative energy metabolism is the process that supports brain activation, refuting both the “aerobic glycolysis” concept and the premise of the “efficiency tradeoff hypothesis”. These studies also shed doubts on the usefulness of the blood oxygenation dependent functional magnetic resonance imaging (BOLD fMRI) method and its signal as an appropriate tool for the estimation of brain oxygen consumption, as it is unable to detect any oxygen present in the extravascular brain tissue. 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

Background: Chemoresistance, particularly to cisplatin, remains a significant challenge in treating high-risk neuroblastoma, resulting in a mere 20% five-year overall survival rate. Tumour-derived small extracellular vesicles (sEVs) have been implicated in cancer progression by promoting angiogenesis, invasion, and proliferation in recipient cells. This study investigated alterations in the protein cargo of sEVs secreted by cisplatin-sensitive and resistant neuroblastoma cells and their impact on reprogramming non-cancerous recipient cells. Methods: sEVs from cisplatin-resistant (KellyCis83) and its cisplatin-sensitive parental cell line (Kelly) were isolated and characterised, followed by proteomic profiling and Gene Set Enrichment Analysis. Functional assays using human umbilical vein endothelial cells (HUVECs) evaluated the effects of sEVs on proliferation, migration, tube formation, and metabolism. The clinical relevance of the shortlisted sEV glycolytic proteins was evaluated using the R2 Genomics Analysis and Visualisation Platform. Results: Proteomic analysis revealed dysregulated metabolic pathways in KellyCis83 sEVs. While Kelly’s and KellyCis83’s sEV-induced aerobic glycolytic rates were similar, oxidative phosphorylation (OXPHOS) was significantly reduced in HUVECs treated with Kelly’s sEVs compared to KellyCis83’s sEVs, which might have been due to an altered balance of glycolytic enzymes in sEVs. Under angiogenic-factor-deprived conditions, the uptake of sEVs by HUVECs reduced their proliferation and increased anchorage-dependent differentiation. Our study demonstrated the enrichment of the MYCN oncogene and clinically relevant glycolytic proteins in neuroblastoma cell-derived sEVs. Conclusions: This study reports a potential mechanism by which sEVs derived from cisplatin-resistant neuroblastoma cells modulate endothelial cell function through alterations in metabolic pathways and provides an opportunity to explore exosomal MYCN and glycolytic proteins as circulating biomarkers for progression and treatment response signatures, using less invasive methods and enabling personalised treatment approaches for neuroblastoma patients. Full article

Background: Small-cell lung cancer (SCLC) is an aggressive malignancy marked by rapid progression, early metastasis, and frequent relapse despite chemotherapy. Due to its genetic complexity, targeted therapies have limited success. Autophagy, a lysosome-dependent cellular degradation process, plays a key role in SCLC, yet effective autophagy-targeting strategies are lacking. This study evaluates Tat-SP4, an autophagy-targeting stapled peptide, for its anti-proliferative effects in SCLC. Method: We assessed Tat-SP4′s impact on autophagy in SCLC cells by measuring p62 and LC3 levels. Mitochondrial function was evaluated via mitochondrial membrane potential (Δψm) and oxygen consumption rate (OCR). Anti-proliferative effects were determined using cell viability assays in vitro and xenograft models in vivo. Cellular uptake mechanisms were investigated using Ca²⁺ imaging and pharmacological inhibitors. Result: Tat-SP4 induced a strong autophagic response and triggered autosis, a form of autophagy-dependent necrotic cell death, impairing SCLC cell proliferation. It also caused mitochondrial dysfunction with impaired oxidative phosphorylation (OXPHOS). Tat-SP4 entered cells predominantly via macropinocytosis, triggering extracellular Ca²⁺ influx measurable by live-cell imaging. Digoxin, an Na⁺, K⁺-ATPase inhibitor, partially reversed the effect of Tat-SP4 on Ca²⁺ influx, cell death, and OXPHOS activity. Lastly, Tat-SP4 inhibited tumor growth in a xenograft-based animal model for SCLC. Conclusions: The autophagy-targeting stapled peptide Tat-SP4 inhibited the proliferation of SCLC cells in vitro and inhibited the growth of the SCLC tumor in vivo. Macropinocytosis facilitates cell entry for Tat-SP4, which can be monitored by influx of extracellular Ca²⁺. By exploiting macropinocytosis for cell entry and converting the pro-survival autophagy process into a death pathway, Tat-SP4 represents a novel therapeutic strategy against SCLC. Full article

Heated tobacco products (HTPs) are marketed as lower-risk alternatives to conventional cigarettes; however, their toxicological impacts remain insufficiently characterized. This study evaluated the effects of HTP emissions on gene expression and mitochondrial function in comparison with conventional cigarettes. Whole cigarette smoke condensates (WCSCs), comprising both gas and particulate phases, were prepared from three commercially available HTPs and from 3R4F reference cigarettes. Human lung epithelial BEAS-2B cells were exposed to WCSCs at 3 μg nicotine/mL for 24 h, followed by transcriptome profiling using RNA sequencing. Principal component analysis demonstrated that HTP-WCSCs induced weaker gene expression changes than 3R4F-WCSC, with only modest variation among HTPs. Gene set enrichment analysis revealed that both HTP- and 3R4F-WCSCs significantly downregulated oxidative phosphorylation (OXPHOS)–related pathways, indicating potential mitochondrial impairment. Functional assays confirmed that both exposures elevated mitochondrial reactive oxygen species (ROS), while mitochondrial morphology, ATP production, membrane potential, and cytosolic ROS were largely unaffected. Collectively, these results show that although HTP emissions elicit weaker transcriptomic perturbations than conventional cigarette emissions, both converge on mitochondrial targets by suppressing OXPHOS gene expression and increasing mitochondrial ROS. Mitochondrial dysfunction may therefore represent a common mechanism underlying tobacco product toxicity. Full article

Chios mastic gum (CMG), derived from the resin of the Pistacia lentiscus has long been considered a natural remedy in the Mediterranean region. Its anti-inflammatory and antioxidant properties have garnered increasing attention from scientists and consumers over recent decades. While substantial evidence supports CMG’s efficacy in preventing and treating common health disorders and its potential as a cancer cell inhibitor, the underlying molecular mechanisms remain poorly understood. In this study, we utilized zebrafish embryos as a model organism to identify molecular pathways modulated by CMG treatment. Embryos were exposed to non-toxic CMG concentrations for 3 to 96 h post-fertilization. LC-HRMS proteomics, combined with enrichment analysis, revealed oxidative phosphorylation (OxPhos), electron transport chain (ETC), and tricarboxylic acid cycle (TCA) as main processes. The latter highlights the benefits of CMG administration in energy generation and cytoskeletal integrity. From the plethora of identified proteins, hierarchical clustering revealed three main antioxidant proteins as upregulated, namely copper-zinc superoxide dismutase, thioredoxin-disulfide reductase, and catalase, confirming the contribution of CMG to the enhancement of zebrafish’s antioxidant defense. Full article

Solar lentigo is a significant dermatological concern affecting individuals of different genders and ethnicities. Its pathogenesis is primarily attributed to chronic ultraviolet (UV) exposure, increased melanogenesis, and disrupted epidermal turnover, leading to the development of hyperpigmented lesions. A major challenge in solar lentigo research is acquiring viable skin tissue, which is crucial for understanding the dynamics of the cellular microenvironment. In the present study, we sought to establish a non-invasive in vivo measurement technique to visualize cellular dynamics associated with solar lentigo. Utilizing fluorescence lifetime imaging microscopy (FLIM), we quantified the decay of NAD(P)H fluorescence lifetime and observed a reduction in oxidative phosphorylation (OXPHOS) activity in solar lentigo lesions compared to adjacent non-lesional skin. To determine whether the observed reduction in OXPHOS activity was due to excessive melanin accumulation in keratinocytes, we developed a melanin deposition model and examined the pleiotropic alterations occurring in keratinocytes following the phagocytosis of excessive melanin. Our findings indicate that excessive melanin deposition downregulates OXPHOS in differentiating keratinocytes and induces senescence-associated phenotypes characterized by perturbed cell cycle progression, increased cell size and aneuploidy, and the secretion of inflammatory mediators in proliferating keratinocytes. Collectively, our results implicate a solar lentigo-specific senescence mechanism driven by excessive melanin accumulation in keratinocytes, providing new insights about the intrinsic modulators of the pathological condition. Full article