Clinical Bioenergetics

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

Tumor cells often exhibit mitochondrial dysfunction and a pronounced glycolytic shift (the “Warburg effect”) that alters the tumor microenvironment. These metabolic changes, including mitochondrial DNA mutations and impaired oxidative phosphorylation, confer survival advantages and can reduce sensitivity to chemotherapeutics such as paclitaxel. In hypoxic environments, cancer cells upregulate glycolysis via HIF-1α, consequently lowering the extracellular pH through lactate secretion, which is associated with resistance to paclitaxel. Likewise, cancer-associated fibroblasts and immune cells undergo metabolic reprogramming in the tumor microenvironment. Glycolytic CAFs produce lactate and pyruvate that fuel tumor cells, reinforcing drug resistance, and tumor-driven polarization of macrophages toward an immunosuppressive M2 phenotype further impairs the anti-tumor response. Here, we review recent findings on how these metabolic adaptations attenuate paclitaxel efficacy and discuss strategies to overcome resistance. We highlight 15 key studies that reported cancer types, metabolic alterations, molecular targets, and outcomes related to paclitaxel response. Overall, the data suggest that targeting metabolic vulnerabilities, for example, by inhibiting glycolysis (HK2, PGAM1, and PDK) or modulating mitochondrial function, may restore paclitaxel sensitivity. Understanding metabolic crosstalk in the tumor microenvironment provides a basis for combined therapies that improve outcomes in paclitaxel-resistant cancers. Full article

Mitochondrial integrity is indispensable for pulmonary cellular homeostasis, with its dysfunction increasingly being implicated as a central mechanism in the etiology of respiratory disorders. We present a comprehensive overview of the integral role played by mitochondrial dynamics, such as fusion, fission, mitophagy, intracellular trafficking, and biogenesis, in maintaining pulmonary homeostasis. This study further explores how perturbations in these processes contribute to the pathogenesis of diverse lung disorders, including chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and drug-induced lung disease. It further explores how perturbations in these processes contribute to the pathogenesis of diverse lung disorders—for example, chronic obstructive pulmonary disease (COPD; responsible for roughly 55% of chronic respiratory disease cases), bronchopulmonary dysplasia (BPD; affecting up to 45% of infants born before 29 weeks of gestation), pulmonary arterial hypertension (PAH; a rare condition causing about 22,000 deaths worldwide in 2021), idiopathic pulmonary fibrosis (IPF; 0.33–4.51 cases per 10,000 persons), and drug-induced lung disease. Evidence demonstrates that mitochondria-triggered apoptosis, metabolic shifts, and subsequent inflammatory signaling act together to drive airway tissue remodeling and fibrotic progression across these lung diseases. Furthermore, this review evaluates the therapeutic potential of mitochondrial-targeted drugs, such as MitoQ and SS31, and metformin, which have shown promise in basic and preclinical studies. Preclinical and early clinical evaluations include an ongoing trial of the mitochondrial-targeted antioxidant MitoQ (NCT02966665, phase 1) in COPD, a 4-month open-label DCA study in PAH patients, and studies determining the preclinical efficacy of SS-31 and metformin in IPF models. Ultimately, integrating mitochondrial biomarkers into clinical practice holds the potential not only to facilitate early disease detection but also to enable the development of precision therapies, thereby offering renewed hope for patients afflicted with chronic lung diseases. Full article

Background/Objectives: Traumatic brain injury (TBI) affects millions of people worldwide, with approximately 2.8 million cases occurring in the United States each year. These injuries may be mild, moderate, or severe based on intensity of impact. The damage caused by TBI results not only from the initial injury, but also from secondary damage due to oxidative stress. Oxidative stress is the increase in reactive oxygen and nitrogen species and the decrease in overall antioxidant capacity, which can lead to a loss of protein function. There is currently no treatment for TBI, only alleviation of symptoms. Glutathione, the most potent antioxidant in the brain, is capable of reducing oxidative damage. Methods: This study investigates the efficacy of gamma-glutamylcysteine ethyl ester (GCEE), a glutathione analog, as a post-therapeutic treatment option in moderate TBI using enzymatic analysis. Enzymatic analysis indicates that key metabolic enzymes of TBI samples treated with GCEE significantly increase in activity relative to traumatically brain injured rats treated with a saline treatment. Protein and gene expression of TBI samples treated with GCEE was also analyzed and compared to that of control and saline-treated samples. Results: Glutathione-related enzymes were found to be increased in GCEE-treated animals compared to saline, thereby showing an increase in antioxidant defense from gamma-glutamylcysteine ethyl ester. Conclusions: Results demonstrate GCEE as a promising post-therapeutic treatment for moderate TBI. Full article

The literature on creatine biomarkers in various bodily fluids remains limited. The purpose of this review is to explore the available data regarding the presence of molecules considered biomarkers of creatine metabolism—namely creatine, guanidinoacetate, and creatinine—across different bodily fluids and matrices. In addition to providing reference values for each biofluid, the paper reports concentrations of these biomarkers in different pathologies. The impairment of creatine metabolism is most extensively studied in creatine deficiency syndromes, which are characterized by genetic deficiencies in either the enzymes involved in creatine biosynthesis or creatine transport. However, other conditions may also influence creatine metabolism to some extent. Our paper also focuses on the transport pathways of these metabolites from their originating tissues to various bodily fluids, typically mediated by the creatine transporter (SLC6A8), with evidence suggesting the involvement of other transporters as well. Gas and liquid chromatography have replaced traditional methods for the analytical detection of biomarkers of creatine metabolism and are now commonly used for this purpose. The paper also discusses the differences and variations between these analytical methods. Full article