Clinical Bioenergetics

Mitochondria are highly dynamic structures that undergo constant remodelling by the process of fission and fusion. Using simulation methods, we study the effects of neuron loss in humans due to the proliferation of deletion mutations. We implement two models of an organelle, namely, closed cristae (CC) and open mitochondrion (OM). With CC, mtDNA are confined to a crista unless mixed by the process of fission and fusion. Conversely, mtDNA can diffuse freely throughout the organelle in the OM model. We also implement selective mitophagy in the CC model. Higher rates of mixing mtDNA increase the rate of neuron loss, a prerequisite for cognitive decline and dementia. Selective mitophagy mitigates the effect of high rate mixing. However, this mitigation is all or nothing. Even at nominal rates of mitophagy compared to higher mixing rates, neuron loss is almost completely eliminated. The results of our model suggest that the role of fission and fusion, in removing defective mtDNA, may be inconsistent with observed patterns of ageing and dementia. The model serves as a hypothesis-generating tool to stimulate experimental re-evaluation of the role of fission and fusion. Full article

Mitochondrial toxicity is a major concern in drug development and safety assessment. Machine learning models trained on mitochondrial membrane potential (MMP) assay data offer promising toxicity predictions, but cross-scaffold and cross-assay transferability remain uncharacterized. We evaluated classical machine learning and deep learning architectures across six molecular representations and both random and scaffold-based splitting strategies, assessing performance on an internal MMP test set and an independent external set comprising flux and glucose–galactose assay data. Across all model configurations, we observed a consistent cross-assay generalization gap, independent of model type, feature choice, or augmentation strategy. Mordred descriptors provided the most transferable predictive signal, outperforming fingerprint-based representations on the external set. SHAP analysis of the best CatBoost and Random Forest models identified autocorrelation-family descriptors as dominant predictors. C3SP3 contributed through feature interactions while ATS5i showed positive association with toxicity across assays. Motif-level and descriptor-level associations proved to be strongly assay-dependent, supporting a mechanism in which mitochondrial toxicity arises from multivariate physicochemical interactions rather than single structural alerts. Full article

Background: Physical inactivity is a major contributor to cardiometabolic disease and mortality. Although mitochondrial dysfunction characterizes overt pathology, whether sedentarism constitutes a distinct and measurable bioenergetic disease state, rather than simply reduced fitness, has not been established. Methods: Nine sedentary (SED) and ten physically active (AC) healthy males (42 ± 14 yr) were studied. Skeletal muscle bioenergetics were assessed using high-resolution respirometry, fluxomics, metabolomics, and protein expression analyses. Whole-body physiology was evaluated using cardiopulmonary exercise and lactate testing (CPELT). Results: At rest, SED exhibited marked reductions in mitochondrial capacity, including Complex I (−36%), Complex II (−28%), electron transport system capacity (−34%), and ATP-synthase-coupled respiration (−30%, all p < 0.01). The most pronounced alteration was a 49% reduction in mitochondrial pyruvate carrier (MPC1) expression, which closely correlated with reduced pyruvate oxidation (−37%, p = 0.006) and lower TCA intermediates. SED also showed reduced MCT1 abundance, impaired fatty-acid oxidation capacity (−32% to −35%), decreased CPT1 activity (−51%), altered cardiolipin composition, and elevated ROS/O₂ flux ratios. During exercise, SED demonstrated lower VO₂max (−38%), reduced fat oxidation (−35%), and higher blood lactate accumulation (>60%, p < 0.001). Mitochondrial function was strongly associated with exercise performance (r = 0.57–0.78, p < 0.01). Conclusions: Healthy sedentary adults displayed a coordinated reduction in tissue-level mitochondrial oxidative capacity, substrate-handling markers, cardiolipin abundance, and metabolic flexibility. These findings should be interpreted as an integrated per-mg skeletal-muscle bioenergetic phenotype in which lower mitochondrial density may account for much of the observed reduction. Within this phenotype, the 49% reduction in MPC1 alongside preserved GLUT4, LDHA, and LDHB abundance represents an outstanding differential observation that future studies with direct mitochondrial-content normalization should test. CPELT-derived fat oxidation and blood lactate responses reflected this tissue-level bioenergetic phenotype, providing candidate noninvasive physiological markers for future longitudinal and interventional studies. Full article

Mitochondria have emerged as critical regulators of cancer biology, transcending their classical role as cellular powerhouses to orchestrate complex metabolic, signaling, and survival pathways essential for tumorigenesis. This review examines the multifaceted role of mitochondria in cancer, integrating initial discoveries with recent advances from recent studies. We explore how mitochondrial DNA mutations, metabolic reprogramming, and alterations in mitochondrial dynamics contribute to malignant transformation, tumor progression, and therapeutic resistance. Mitochondrial dysfunction, long considered a consequence of the Warburg effect, is now recognized as an active driver of oncogenesis through retrograde signaling, oxidative stress modulation, and tumor microenvironment remodeling. The review highlights emerging therapeutic strategies targeting mitochondrial metabolism, including inhibitors of oxidative phosphorylation, mitochondrial-targeted drugs, and approaches exploiting metabolic vulnerabilities. Understanding the complex interplay between mitochondrial function and cancer biology provides a foundation for developing novel diagnostic biomarkers and precision oncology approaches. Full article

Cutaneous melanoma is the most lethal form of skin cancer because of its aggressiveness, rapid metastasis, and high therapeutic resistance. The 2018 World Health Organization (WHO) classification emphasized that melanoma comprises distinct subtypes defined by cumulative sun damage, site of origin, and molecular characteristics, which explain differences in mutational burden, immunogenicity, and treatment response. Immunotherapy with anti-PD-1 therapy such as nivolumab and pembrolizumab changed the therapeutic landscape by restoring CD8+ T-cell activity and improving survival. Still, many patients show primary or acquired resistance influenced by low PD-L1 expression, loss of antigen presentation, tumor metabolic plasticity, and an immunosuppressive microenvironment. Mitochondria are central to this process. They regulate ATP generation through oxidative phosphorylation (OXPHOS), redox control, apoptosis, and the metabolic programming needed for T-cell activation. In the tumor microenvironment (TME), hypoxia, nutrient restriction, and PD-1 signaling reduce mitochondrial biogenesis, increase fission and reactive oxygen species (ROS) accumulation, and lead to exhaustion and impaired effector function. Moreover, tumor cells outcompete immune cells for key nutrients such as glucose and glutamine, while increased lactate production and extracellular acidosis further suppress mitochondrial respiration in T cells. Strategies to overcome resistance include restoring oxidative metabolism, activating PGC-1α, supplying metabolic substrates, and combining checkpoint blockade with inhibitors of glycolysis or glutaminolysis to enhance the immune response. Full article

(1) Background: Mild traumatic brain injury (mTBI), the most prevalent form of traumatic brain injury, often results from repetitive impacts to the head and is associated with long-term neurological impairment. The pathophysiology of mTBI is multifactorial and involves alterations in mitochondrial bioenergetics, a key determinant of neuronal function and survival. Although mitochondrial dysfunction is recognized as a hallmark of mTBI, its long-term effects on bioenergetics and the roles of regulatory cytosolic and mitochondrial proteins remain poorly understood. We hypothesized that repeated mTBI (rmTBI) induces sustained deficits in mitochondrial bioenergetics that are associated with long-term changes in key bioenergetic and other regulatory proteins. (2) Methods: Using the repeated CHIMERA injury model in adult male rats, randomly assigned to sham or rmTBI groups, we assessed mitochondrial respiration in isolated mitochondria and whole cerebral cortex homogenates using a Clark O₂ electrode and an Oroboros O₂k respirometer at time points ranging from 1 day to 2 months post-injury. Western blotting was performed for expression of regulatory proteins HKI, DRP1, MFN2, VDAC1, and ANT2. (3) Results: At 2 months post-rmTBI, respiration was faster and uncoupled, while ATP synthesis was significantly slowed compared with sham rats. This was accompanied by decreased expression of mitochondrial MFN2 and ANT2, by increased mitochondrial expression of DRP1, and by decreased translocation of HKI to mitochondria. There was no significant difference in VDAC1 expression. Earlier time points showed no significant differences in bioenergetics or protein expression, but neuro-inflammatory markers (GFAP and Iba1) were significantly elevated at these earlier time points of post-injury. (4) Conclusions: These findings indicate that rmTBI leads to a delayed long-term impairment of mitochondrial bioenergetics associated with alterations in proteins critical for bioenergetic regulation and mitochondrial control. This suggests a pathophysiologic mechanism for the persistent cognitive and behavioral deficits observed following rmTBI. Full article

Background: Metabolic syndrome is associated with early impairments in cellular bioenergetics that are not fully captured by conventional body composition measures. Molecular hydrogen, produced endogenously through gut microbial fermentation and measurable in breath, has been implicated in redox and mitochondrial regulation. Whether breath hydrogen relates to preservation of intracellular, metabolically active tissue in metabolic syndrome remains unclear. Objectives: To examine the association between breath hydrogen concentration and an integrated cellular bioenergetic phenotype derived from intracellular body composition indices in sedentary adults with metabolic syndrome. Methods: Twenty-eight sedentary, middle-aged adults (51.2 ± 7.9 years, 19 females) with metabolic syndrome underwent fasting breath hydrogen assessment and multifrequency bioelectrical impedance analysis. A composite cellular bioenergetic phenotype was derived using principal component analysis of body cell mass, intracellular water, total body potassium, and glycogen. Associations between breath hydrogen and the composite phenotype were evaluated using Spearman correlation with bootstrapped confidence intervals, Theil-Sen regression, and Bayesian linear regression adjusted for age, sex, and waist circumference. Sensitivity analyses included fat-free mass. Results: A single principal component explained 98.6% of the variance across intracellular variables, indicating a highly coherent cellular bioenergetic phenotype. Breath hydrogen concentration was positively associated with this phenotype (ρ = 0.43, p = 0.021; BCa 95% CI 0.07–0.70). Theil-Sen regression confirmed a robust positive association (β = 0.017 per ppm hydrogen; 95% CI 0.002–0.046). Bayesian models showed posterior distributions centered on positive effect sizes, independent of central adiposity. In contrast, the association with fat-free mass alone was borderline. Conclusions: Breath hydrogen concentration reflects an integrated intracellular bioenergetic phenotype in sedentary adults with metabolic syndrome, tracking cellular quality rather than lean mass quantity. Breath hydrogen may serve as a non-invasive biomarker of cellular bioenergetic integrity and a potential tool for phenotype-guided metabolic interventions. Full article

Energy homeostasis arises from a complex interplay between gut-derived hormones, the central nervous system, and pancreatic function. Beyond the classical incretin axis, a broad spectrum of gut peptides acts in concert to coordinate appetite regulation, nutrient sensing, gastric motility, and systemic bioenergetic balance. Perturbation of this network contributes to metabolic disorders such as obesity, type 2 diabetes, and cachexia, underscoring its pivotal role in physiological and pathological energy regulation. This review provides an integrated analysis of the mechanisms through which gut–brain–pancreas communication maintains metabolic homeostasis, with particular attention to the dynamic cross-talk between peripheral endocrine signals and central regulatory circuits. Alterations in these pathways are examined in relation to their impact on energy expenditure and substrate utilisation, alongside recent translational efforts exploiting multi-receptor peptide agonism and combinatorial hormonal modulation to restore metabolic equilibrium. Emerging therapeutic approaches increasingly aim to engage multiple bioenergetic pathways simultaneously, supported by advances in peptide engineering and molecular design. By conceptualising metabolic regulation as a coordinated network rather than a linear hormonal cascade, this article delineates a physiological and translational framework for next-generation interventions targeting bioenergetic dysfunction in human disease. Full article

Vascular inflammation and endothelial dysfunction are key drivers in the development of cardiovascular and neurovascular diseases. Mitochondrial dysfunction and oxidative stress further amplify inflammatory cascades, emphasising the need for targeted strategies that restore endothelial homeostasis at the subcellular level. Hydrogen sulphide (H₂S) donors, such as AP39, offer cytoprotective benefits but are limited by short half-life and rapid release of the active compound, H₂S. We developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating AP39 (PLGA-AP39) to achieve sustained, mitochondria-targeted H₂S delivery. Nanoparticles were characterised by size, polydispersity, zeta potential, encapsulation efficiency, and in vitro release kinetics. Human umbilical vein endothelial cells (HUVEC) were exposed to TNF-α to induce inflammation, followed by treatment with free AP39 or PLGA-AP39. Anti-inflammatory effects were assessed by measuring IL-6, IL-8, and TGF-β levels. Mitochondrial function was evaluated using a Seahorse XFe24 Analyser, membrane potential assays, and mitochondrial ROS detection. Moreover, we investigated vascular function by analysing capillary-like tube formation and wound closure in response to treatments. PLGA-AP39 nanoparticles displayed a uniform size (~227 nm), low PDI, and high encapsulation efficiency (>78%). Sustained AP39 release was observed over seven days. Treatment with PLGA-AP39 significantly restored TNF-α-induced endothelial dysfunction and reduced TNF-α-induced release of IL-6, IL-8, and TGF-β compared to untreated controls. Seahorse analysis revealed restoration of maximal respiration and increased spare respiratory capacity. Encapsulated AP39 also preserved mitochondrial membrane potential and reduced mitochondrial ROS production, demonstrating enhanced protection against inflammation-induced metabolic dysfunction. This work establishes a novel nanoparticle-based strategy for prolonged, mitochondria-specific H₂S delivery to counteract vascular inflammation and enhance endothelial bioenergetics. The results from this work are pioneering in the generation of a novel delivery method for H₂S donors employing PLGA and represent a promising therapeutic avenue for treating chronic vascular inflammatory disorders. Full article

The impairment of biological tissue caused by ischemia is a key area of research in both natural sciences and medical research. The utilization of oxygen in the process of tissue respiration is closely linked to mitochondrial function, i.e., the directed transfer of electrons between the enzyme complexes of the respiratory chain. The Cytochrome c oxidase, complex IV of the ETC, represents the so-called “rate-limiting step.” Kadenbach’s theory has described different activity states of this enzyme, which are crucial for the production of oxygen radicals. This mechanism is an important part of understanding ischemic damage to the heart. Full article

Objective: Resistance exercise can induce muscle damage that impairs sports performance and cellular repair. Myokines, particularly mitochondrial myokines, play an important role in regulating energy metabolism and muscle recovery. The ACTN3 R577X polymorphism, which alters the expression of α-actinin-3 in muscle fibers, may influence myokine responses by modulating exercise adaptation and recovery. Methods: Seventy-five amateur runners (30–55 years) from the São Paulo International Marathon were evaluated. Plasma levels of mitochondrial myokines (BDNF, FGF-21, FSTL, IL-6, apelin, IL-15, musclin, and myostatin) were measured before and after the race and correlated with ACTN3 R577X genotypes. Results: In this study, the genotypic frequencies of the ACTN3 R577X polymorphism were 36% (RR), 39% (RX), and 14% (XX). Plasma concentrations of BDNF, FSTL, FGF-21, and IL-6 increased immediately after running across all genotypes, with no significant differences observed between genotypes. In contrast, plasma levels of myostatin, musclin, IL-15, and apelin decreased during the recovery period only among runners carrying the R allele. Conclusions: Mitochondrial myokine responses to resistance exercise were not substantially different among genotypes of the ACTN3 R577X polymorphism. However, myokines associated with protein breakdown and bioenergetic adaptation were reduced during the recovery period in runners carrying the R allele, which may impact muscle repair and bioenergetic adaptation. 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

A constantly increasing incidence of chronic diseases is a challenge for healthcare worldwide, being directly associated with physical inactivity, which is considered an important cause of most chronic diseases. In contrast, physical exercise has been proven as a powerful instrument of healthcare to protect individuals against health-to-disease transition and against disease progression. Nonetheless, a number of studies warn against inappropriate high-intensity and/or unaccustomed exercise that exceeds an individual’s physical capacity. Indeed, extensive cardiac activity during prolonged exercise leads to significantly increased cardiac dimensions, triggering cardiac complications that may result in arrhythmogenic sudden cardiac death. The remarkable plasticity of mitochondria allows these organelles to sense and adapt to a variety of stressors and respond to stimuli by molecular signalling, regulating bioenergetics and cellular homeostasis, decisive for repair processes, proliferation, apoptosis, and tissue regeneration to combat degeneration, with whole body outcomes. Mitochondria act as biosensors in the human body; they are reactive to stimuli and protective against health-to-disease transition. To perform this life-important function throughout life, mitochondria need supportive measures, including physical activity, considered an essential pillar of mitochondrial medicine. This article highlights reciprocity between the quality of mitochondrial health and homeostasis on one hand and physical fitness and exercise intervention on the other hand. The proposed novelty relates to the monitoring of mitochondrial homeostasis, which is strongly recommended for creating individualised training programmes, and monitoring exercise efficacy during and after the programme is completed. To this end, a patient-friendly non-invasive approach is already established, utilising tear fluid multi-omics, mitochondria as the vital biosensors, and AI-based multi-professional data interpretation. Full article

Background: Chronic rhinosinusitis (CRS) affects nearly 9% of the global population with a rising incidence over recent decades. Neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease pose significant global burden, and emerging evidence suggests pathophysiological links through shared bioenergetic dysfunction, peripheral-to-central inflammatory signaling, and altered nasal microbiota. This review evaluates the evidence for CRS as a potentially modifiable peripheral contributor to neurodegenerative disease progression. Methods: A systematic review was conducted using PubMed, Cochrane, Web of Science, Embase, and CENTRAL from January 2000 to July 2025. Search terms included “Chronic Rhinosinusitis,” “Neurodegeneration,” “Mild Cognitive Impairment,” “Alzheimer’s Disease,” “Parkinson’s Disease,” “Bioenergetics,” and “Microbiome.” Clinical and experimental studies exploring epidemiological links, mechanistic pathways, biomarkers, and therapeutic targets were included. Results: Twenty-one studies involving over 100,000 participants met the inclusion criteria. Existing meta-analytic evidence demonstrated significant associations between CRS and cognitive impairment, with patients scoring approximately 9% lower on global cognitive measures than controls. However, other large-scale cohort studies did not pinpoint an increased dementia incidence, suggesting CRS may contribute to early, potentially reversible cognitive decline without directly driving dementia onset. Neuroimaging studies revealed altered frontoparietal connectivity and orbitofrontal hyperactivity in CRS patients. Mechanistic studies support peripheral inflammatory cytokines disrupting the blood–brain barrier, autonomic dysfunction impairing mucociliary clearance, microbiome-driven amyloid cross-seeding, and compromised cerebrospinal fluid clearance via olfactory–cribriform pathways. Discussion: Evidence supports complex, bidirectional relationships between CRS and neurodegeneration characterized by convergent inflammatory, autonomic, and bioenergetic pathways. Therapeutic strategies targeting sinonasal inflammation, microbiome dysbiosis, and mitochondrial dysfunction represent promising intervention avenues. Recognizing CRS as a treatable factor in neurodegenerative risk stratification may enable earlier diagnosis and prevention strategies. Full article

Nicotinamide adenine dinucleotide (NAD+) is an important coenzyme essential for metabolism, energy production, gene regulation, and cellular communication. With aging, NAD+ levels decrease, which may be partly responsible for age-related disease and impaired function. While certain lifestyle practices may help to maintain NAD+, such as intermittent fasting, exercise, and reduced alcohol consumption, these activities do not appear to support optimal NAD+ levels. For this reason, numerous dietary supplements have emerged, with the claim of increasing NAD+ levels and resulting in improved health and, possibly, increased longevity. Such agents include NAD+, as well as the NAD+ precursors niacin, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). This article discusses the scientific rationale and evidence for using such supplements, with a particular emphasis on human oral ingestion and associated health outcomes. The current literature has been reviewed, and practical applications are presented. Full article

Traditionally, referred to as the “Powerhouse of the Eukaryotic Cell”, mitochondria are essential for host defense in addition to producing ATP. Through processes like mitochondrial antiviral signaling (MAVS), the generation of reactive oxygen species (ROS), and the modification of inflammatory pathways, they respond to bacterial, fungal, viral, and parasitic infections while coordinating immune signaling, controlling cell death, and detecting pathogens. Pathogens, on the other hand, have developed ways to interfere with or harm mitochondrial function, which results in oxidative stress, cell death, altered metabolism, and compromised immune signaling. This type of mitochondrial dysfunction impairs the removal of infections and is linked to tissue damage, chronic inflammation, and long-term health issues. The dual roles of mitochondria in infection are highlighted in this review, which looks at both their defense mechanisms and the ways in which pathogens use them to increase their chances of survival. Full article

Vanadium is a transition metal whose environmental presence has increased due to human activities such as fossil fuel combustion and industrial processes. A central mechanism of its toxicity involves mitochondrial dysfunction, as vanadium exposure disrupts energy metabolism, enhances reactive oxygen species (ROS) generation, and triggers oxidative stress, ultimately leading to genetic damage and alterations in cellular signaling. These mitochondrial alterations contribute to its potential carcinogenic, immunotoxic, and neurotoxic properties, affecting multiple systems, including the neurological, renal, immune, and reproductive systems. Since there are no specific treatments for vanadium intoxication, natural compounds—particularly plant-derived metabolites with antioxidant, mitochondrial-targeted, and chelating properties—have been investigated as potential therapeutic agents to counteract its toxicity. In this context, simple models such as the nematode Caenorhabditis elegans (C. elegans), the fruit fly (Drosophila melanogaster), and the zebrafish (Danio rerio) have emerged as valuable experimental systems for studying vanadium-induced mitochondrial dysfunction and evaluating protective strategies. These organisms offer key advantages, including a short life cycle, ease of handling, and conservation of essential biological pathways with mammals, making them effective tools in environmental toxicology. The aim of this review is to outline the mitochondrial-related toxic effects of vanadium across different biological models and to explore plant-based therapeutic approaches capable of mitigating its harmful health impacts. We also propose the use of simple models, such as D. melanogaster, D. rerio, and, most notably, C. elegans, as versatile and complementary experimental platforms to advance research in this field. Full article

Psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia are now recognized as complex systemic conditions in which mitochondrial dysfunction and oxidative stress are key contributors to their pathophysiology. Mitochondria, beyond their role in ATP synthesis, are critical for calcium regulation, immune responses, and apoptosis, and their impairment affects brain function. This review examines current evidence from transcriptomics, metabolomics, neuroimaging, and preclinical studies, which consistently show disruptions in oxidative phosphorylation, mitochondrial fragmentation, altered mitochondrial DNA, and heightened inflammatory activity across these disorders. We integrate recent advances with the understanding of mitochondrial bioenergetics in the brain, the contribution of redox imbalance to neural dysfunction, the crosstalk between mitochondria and immune mechanisms, and the relevance of these processes to clinical symptoms. Furthermore, we highlight the promise of bioenergetic biomarkers and emerging interventions targeting mitochondrial pathways, including antioxidants, AMPK-SIRT1-PGC-1α axis modulators, physical exercise, and mitoprotective agents. Peripheral metabolic signatures and neuroimaging modalities are also discussed as tools for diagnostic refinement and individualized therapeutic approaches. These insights underscore the centrality of mitochondrial health in psychiatric disease and support the development of precision psychiatry grounded in metabolic phenotyping. Full article