OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Янв. 12, 2023

Abstract Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present fatigue and multi-system disorders, are often lean, die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients diseases ( n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism . We examine phenomenon longitudinally in patient-derived fibroblasts multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular expenditure. This cell-autonomous occurs despite near-normal coupling efficiency, excluding uncoupling as general mechanism. Instead, is associated DNA instability, activation integrated stress response (ISR), increased extracellular secretion age-related cytokines metabokines including GDF15. In parallel, accelerate telomere erosion epigenetic aging per cell division, consistent excess expenditure accelerates biological aging. To explore potential mechanisms effects, generate longitudinal RNASeq methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, findings highlight need to understand how influence energetic cost living, link between cells diseases.

Язык: Английский

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Hypermetabolism and energetic constraints in mitochondrial disorders

Nature Metabolism, Год журнала: 2024, Номер 6(2), С. 192 - 195

Опубликована: Фев. 9, 2024

Язык: Английский

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Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging

Psychoneuroendocrinology, Год журнала: 2023, Номер 155, С. 106322 - 106322

Опубликована: Июнь 15, 2023

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic results in load, dysregulated state predicts functional decline, accelerates aging, and increases mortality humans. The energetic cost cellular basis for damaging effects load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find glucocorticoid exposure energy expenditure ~60%, along with metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This stress-induced hypermetabolism is linked mtDNA instability, non-linearly affects age-related cytokines secretion, aging based on DNA methylation clocks, telomere shortening rate, reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing exacerbates accelerated phenotype, pointing total as potential driver dynamics. Together, our findings define bioenergetic multi-omic recalibrations stress adaptation, underscoring increased interrelated features load.

Язык: Английский

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Nutritional Strategies in the Rehabilitation of Musculoskeletal Injuries in Athletes: A Systematic Integrative Review

Nutrients, Год журнала: 2023, Номер 15(4), С. 819 - 819

Опубликована: Фев. 5, 2023

It is estimated that three to five million sports injuries occur worldwide each year. The highest incidence reported during competition periods with mainly affectation of the musculoskeletal tissue. For appropriate nutritional management and correct use supplements, it important individualize based on clinical effects know adaptive response rehabilitation phase after a injury in athletes. Therefore, aim this PRISMA Exercise, Rehabilitation, Sport Medicine Sports Science PERSiST-based systematic integrative review was perform an update strategies elite After searching following databases: PubMed/Medline, Scopus, PEDro, Google Scholar, total 18 studies met inclusion criteria (Price Index: 66.6%). risk bias assessment for randomized controlled trials performed using RoB 2.0 tool while articles were evaluated AMSTAR items. Based main findings selected studies, benefit process injured athletes include balanced energy intake, high-protein carbohydrate-rich diet. Supportive supervision should be provided avoid low availability. potential supplementation collagen, creatine monohydrate, omega-3 (fish oils), vitamin D requires further research although are quite promising. worth noting lack higher number reviews last 10 years. analyzing current quantitative non-quantitative evidence, we encourage researchers conduct evaluating doses discussed nutrients confirm findings, but also follow international guidelines at time scientific literature.

Язык: Английский

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Psychosocial experiences are associated with human brain mitochondrial biology

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(27)

Опубликована: Июнь 18, 2024

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position both as targets drivers psychosocial experiences. On one hand, chronic stress exposure mood states may alter multiple aspects mitochondrial biology; other functional variations in OxPhos capacity social behavior, reactivity, mood. But are exposures subjective linked to biology human brain? By combining longitudinal antemortem assessments factors with postmortem (dorsolateral prefrontal cortex) proteomics older adults, we find that higher well-being is greater abundance machinery, whereas negative lower protein content. Combined, positive explained 18 25% variance complex I, primary biochemical entry point energizes mitochondria. Moreover, interrogating psychobiological specific neuronal nonneuronal cells single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific for glia opposite neurons. As a result, “mind-mitochondria” were masked bulk RNA-seq, highlighting likely underestimation true effect sizes tissues. Thus, self-reported phenotypes.

Язык: Английский

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Allostatic Interoceptive Overload Across Psychiatric and Neurological Conditions

Biological Psychiatry, Год журнала: 2024, Номер 97(1), С. 28 - 40

Опубликована: Июль 2, 2024

Язык: Английский

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Glucocorticoid and Adrenergic Receptor Distribution Across Human Organs and Tissues: A Map for Stress Transduction

Psychosomatic Medicine, Год журнала: 2024, Номер 86(2), С. 89 - 98

Опубликована: Янв. 8, 2024

ABSTRACT Objective Psychosocial stress is transduced into disease risk through energy-dependent release of hormones from the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes. The levels glucocorticoid adrenergic hormones, together with sensitivity tissues to their signaling, define responses. To understand existing pathways responsible for psychobiological transduction stressful experiences, we provide a quantitative whole-body map receptor (AR) expression. Methods We systematically examined gene expression (GR), α- β-ARs (AR-α1B, AR-α2B AR-β2, AR-β3), across 55 different organs using Human Protein Atlas Proteome Map datasets. Given that mitochondria produce energy required respond stress, leveraged MitoCarta3.0 data examine link between hormone density mitochondrial Finally, tested functional interplay GR activation AR in human fibroblast cells. Results was expressed ubiquitously all investigated organ systems, whereas subtypes showed lower more localized patterns. Receptor co-regulation, meaning correlated multiple receptors, found AR-α1B, as well AR-α1B AR-α2B. In cultured fibroblasts, activating selectively increased AR-β2 Consistent known energetic cost responses, expressions were positively associated specific pathways. Conclusions Our results cartography body. Because stress-induced signaling triggers energetically expensive cellular involving energy-transforming mitochondria, tissue-specific co-expression patterns may part determine resilience or vulnerability systems.

Язык: Английский

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Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload

Journal of Experimental Biology, Год журнала: 2024, Номер 227(Suppl_1)

Опубликована: Март 7, 2024

ABSTRACT Exposure to stress during early life may alter the developmental trajectory of an animal by a mechanism known as adaptive plasticity. For example, enhance reproductive success in adverse environment, it is that animals accelerate their growth development. However, these short-term fitness benefits are often associated with reduced longevity, phenomenon rate–lifespan trade-off. In humans, exposure compromises health later and increases disease susceptibility. Glucocorticoids (GCs) major hormones implicated processes. This Review discusses evidence for GC-mediated plasticity development, leading allostatic overload life. We focus on GC-induced effects brain structure function, including neurogenesis; highlight need longitudinal studies; discuss approaches identify molecular mechanisms mediating alteration adult dysfunctions. Further understanding how GC can trajectories at cellular level critical importance reduce burden mental physical ill across course.

Язык: Английский

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To promote healthy aging, focus on the environment

Nature Aging, Год журнала: 2023, Номер 3(11), С. 1334 - 1344

Опубликована: Ноя. 9, 2023

Язык: Английский

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Examining the Interaction between Exercise, Gut Microbiota, and Neurodegeneration: Future Research Directions

Biomedicines, Год журнала: 2023, Номер 11(8), С. 2267 - 2267

Опубликована: Авг. 14, 2023

Physical activity has been demonstrated to have a significant impact on gut microbial diversity and function. Emerging research revealed certain aspects of the complex interactions between gut, exercise, microbiota, neurodegenerative diseases, suggesting that changes in metabolic function may an onset progression neurological conditions. This study aimed review current literature from several databases until 1 June 2023 (PubMed/MEDLINE, Web Science, Google Scholar) interplay physical neurodegeneration. We summarized roles exercise microbiota neurodegeneration identified ways which these are all connected. The gut–brain axis is multifaceted network gained considerable attention recent years. Research indicates plays vital shifts during physiological or pathophysiological conditions diseases; therefore, they closely related maintaining overall health well-being. Similarly, shown positive effects brain cognitive function, reduce/delay severe disorders. Exercise associated with various neurochemical changes, including alterations cortisol levels, increased production endorphins, endocannabinoids like anandamide, as well higher levels serotonin dopamine. These linked mood improvements, enhanced sleep quality, better motor control, enhancements resulting exercise-induced effects. However, further clinical necessary evaluate bacteria taxa along age- sex-based differences.

Язык: Английский

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