Search Results (6)

Mitochondrial reactive oxygen species (mtROS) are central regulators of cellular function, yet their biological roles are often reduced to an oxidative-stress/antioxidant dichotomy. This review reframes mtROS through the concept of mitohormesis, in which outcomes are neither inherently harmful nor beneficial but are determined by a defined set of contextual variables. We present a mechanistic framework in which mtROS effects depend on chemical species identity, sub-mitochondrial site of production, temporal dynamics, redox-buffering capacity, and metabolic state; together, these variables determine whether mtROS promote adaptive eustress or pathological distress. We then show that, across polyphenols, isothiocyanates, terpenoids, alkaloids, and quinones, the biologically relevant effects of natural redox-modulating compounds are mediated less by direct radical scavenging than by pro-hormetic mechanisms, including mild electron transport chain perturbation, nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) activation, modulation of mitochondrial membrane potential, mitochondrial quality control, and NAD⁺/NADPH regulation. Applying this framework to disease reveals strong tissue and state dependence: neurodegeneration favors buffering expansion and mitophagy; metabolic disease may benefit from exercise-mimetic and NRF2-activating strategies; cardiovascular disease illustrates mitohormesis through ischemic preconditioning and CoQ10 supplementation; and cancer requires distinction between prevention and therapy because redox buffering can either protect normal tissue or support tumor survival. Finally, we argue that the failure of non-specific antioxidant supplementation is mechanistically predictable and propose context-aware, biomarker-guided, temporally optimized, and compartment-targeted redox interventions as a more rational translational path. Full article

Background/Objectives: Skeletal muscle adaptation to metabolic stress involves a coordinated regulation of inflammatory, bioenergetic, and anabolic signalling pathways. This study aimed to investigate the potential role of whey protein isolate (WPI; commercial name: Volapure) as a modulator of cellular responses to stress in an in vitro model of exercise-mimetic stress over time. Methods: Murine C2C12-differentiated cells were exposed to an Exercise–Mimetic Mix (ExM) to reproduce key biochemical features of muscle stress. Cells were treated with WPI (1 mg/mL) using Pre-exposure (Pre-ExM) and Post-exposure (Post-ExM) protocols at 8 and 24 h. Multiple endpoints were assessed, including cell viability, reactive oxygen species (ROS) production, cytokine release (TNF-α, IL-6, IL-17), intracellular signalling pathways (p38 MAPK, ERK, AMPK, mTOR), bioenergetic markers (ATP, glycogen, lactate), protein synthesis (OPP incorporation), and Ca²⁺/Mg²⁺ fluxes. Results: ExM exposure induced a stress phenotype characterised by increased oxidative and inflammatory markers, impaired bioenergetic status, and reduced anabolic signalling. WPI was associated with modulation of these responses, reducing ROS and pro-inflammatory cytokines, restoring ATP and glycogen levels, and changes in ERK and mTOR-related signalling. The Post-ExM protocol showed greater modulation compared to the Pre-ExM approach, particularly at 24 h. WPI was also associated with the normalisation of ExM-altered Ca²⁺/Mg²⁺ fluxes. These findings should be interpreted as associative rather than causal. Conclusions: WPI was associated with modulation of key pathways involved in cellular adaptation to metabolic stress, supporting recovery of bioenergetic balance and anabolic signalling in C2C12 cells. These findings suggest a potential role for WPI in influencing cellular responses to metabolic stress, supporting recovery of bioenergetic balance and anabolic signalling in C2C12-differentiated-cells. However, further studies are required to confirm the translational relevance of these observations. Full article

Male infertility is an escalating global health issue, frequently associated with metabolic problems like obesity, diabetes, and age. Recent evidence designates AMP-activated protein kinase (AMPK) as a pivotal regulator linking energy balance to male reproductive function. AMPK regulates essential activities such as spermatogenesis, metabolic support of Sertoli cells, and steroidogenesis in Leydig cells, as well as sperm motility, capacitation, and the acrosome reaction. At the molecular level, AMPK coordinates signaling networks that include mTOR, SIRT1, PGC-1α, and FOXO to modulate mitochondrial function, oxidative stress, and autophagy-related quality control. Dysregulation of AMPK during metabolic and environmental stress results in compromised spermatogenesis, diminished sperm quality, mitochondrial malfunction, and reduced testosterone synthesis. Targeting AMPK signaling constitutes a possible therapeutic approach for enhancing male reproductive health. Pharmacological agents like metformin and AICAR, together with natural bioactive substances, lifestyle modifications, and exercise mimetics, have shown promise in reestablishing metabolic equilibrium and improving reproductive results. Moreover, combinatorial strategies that integrate antioxidants and autophagy modulators may yield synergistic advantages. Nonetheless, obstacles concerning tissue selectivity, optimum dose, and clinical translation persist. Future perspectives highlight precision medicine, biomarker-directed therapies, and the incorporation of metabolic health into fertility treatment. AMPK-targeted treatments collectively provide a novel and mechanistically sound method for addressing male infertility. Full article

Beyond their classical role as “cellular powerhouses”, mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics—including fusion–fission balance, mitophagy–biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion—contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions. Full article

Background/Objectives: Growth in the aging world population is accompanied by an increase in comorbidities, profoundly impacting the quality of life of older people. This development has motivated a large effort to investigate the mechanisms underlying aging and the search for countermeasures. The most investigated strategies envisage the control of diet and physical exercise, which exploit both common and distinct mechanisms to promote health. Since the application of nutritional and exercise protocols to aged persons introduces several issues due to their disabled state, some strategies have been developed. The nutritional approach exploits a wide range of compounds, including calorie restriction mimetics, supplements, antioxidants, and others. In the context of exercise, in recent years, molecules able to provide similar effects to exercise, the so-called exercise mimetics, have been developed. Methods: To have a better perspective on exercise mimetics and their connection with nutrition, we performed a systematic search of the PubMed and Scopus databases using the term “exercise mimetics”. Results: In total, 97 research articles were selected and discussed. The present review provides evidence of the presence of multiple exercise-mimetic compounds and physical strategies that can target metabolic pathways, oxidative stress defense mechanisms, or myokine modulation. Conclusions: Interestingly, this review highlights that an important number of exercise mimetics are represented by products of natural origin and supplements assimilable with diet. This evidence provides a further link between exercise and nutrition and confers a central role on nutrition in the context of exercise mimetics. Full article

Tumor necrosis factor (TNF) binding to endothelial TNF receptor-I (TNFR-I) facilitates monocyte recruitment and chronic inflammation, leading to the development of atherosclerosis. In vitro data show a heightened inflammatory response and atherogenic potential in endothelial cells (ECs) from African American (AA) donors. High laminar shear stress (HSS) can mitigate some aspects of racial differences in endothelial function at the cellular level. We examined possible racial differences in TNF-induced monocyte adhesion and TNFR1 signaling complex expression/activity, along with the effects of HSS. Tohoku Hospital Pediatrics-1 (THP-1) monocytes were used in a co-culture system with human umbilical vein ECs (HUVECs) from Caucasian American (CA) and AA donors to examine racial differences in monocyte adhesion. An in vitro exercise mimetic model was applied to investigate the potential modulatory effect of HSS. THP-1 adherence to ECs and TNF-induced nuclear factor kappa B (NF-κB) DNA binding were elevated in AA ECs compared to CA ECs, but not significantly. We report no significant racial differences in the expression of the TNFR-I signaling complex. Application of HSS significantly increased the expression and shedding of TNFR-I and the expression of TRAF3, and decreased the expression of TRAF5 in both groups. Our data does not support TNF-induced NF-κB activation as a potential mediator of racial disparity in this model. Other pathways and associated factors activated by the TNFR1 signaling complex are recommended targets for future research. Full article