Mitochondrial signal transduction

Cell Metabolism, Год журнала: 2022, Номер 34(11), С. 1620 - 1653

Опубликована: Ноя. 1, 2022

The analogy of mitochondria as powerhouses has expired. Mitochondria are living, dynamic, maternally inherited, energy-transforming, biosynthetic, and signaling organelles that actively transduce biological information. We argue the processor cell, together with nucleus other they constitute mitochondrial information processing system (MIPS). In a three-step process, (1) sense respond to both endogenous environmental inputs through morphological functional remodeling; (2) integrate network-based physical interactions diffusion mechanisms; (3) produce output signals tune functions systemically regulate physiology. This input-to-output transformation allows metabolic, biochemical, neuroendocrine, local or systemic enhance organismal adaptation. An explicit focus on signal transduction emphasizes role communication in biology. framework also opens new avenues understand how mediate inter-organ processes underlying human health.

Язык: Английский

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Mitochondria: It is all about energy

Frontiers in Physiology, Год журнала: 2023, Номер 14

Опубликована: Апрель 25, 2023

Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron calcium homeostasis the of hormones neurotransmitters, such as melatonin. They enable influence communication at all physical levels through interaction with other organelles, nucleus, outside environment. The literature suggests crosstalk between mitochondria circadian clocks, gut microbiota, immune system. might even be hub supporting integrating activity across these domains. Hence, they (missing) link Mitochondrial dysfunction related metabolic syndrome, neuronal diseases, cancer, cardiovascular infectious inflammatory disorders. In this regard, diseases Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), pain are discussed. This review focuses on understanding mitochondrial action that allow for maintenance pathways toward dysregulated mechanisms. Although have allowed us adapt changes over course evolution, turn, evolution has shaped mitochondria. Each evolution-based intervention influences its own way. use physiological stress triggers tolerance stressor, achieving adaptability resistance. describes strategies could recover functioning providing comprehensive, root-cause-focused, integrative approach recovering treating people suffering diseases.

Язык: Английский

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The energetic cost of allostasis and allostatic load

Psychoneuroendocrinology, Год журнала: 2022, Номер 146, С. 105951 - 105951

Опубликована: Окт. 8, 2022

Chronic psychosocial stress increases disease risk and mortality, but the underlying mechanisms remain largely unclear. Here we outline an energy-based model for transduction of chronic into over time. The energetic allostatic load (EMAL) emphasizes cost allostasis load, where "load" is additional burden required to support stress-induced energy needs. Living organisms have a limited capacity consume energy. Overconsumption by brain-body processes leads hypermetabolism, defined as excess expenditure above organism's optimum. In turn, hypermetabolism accelerates physiological decline in cells, laboratory animals, humans, may drive biological aging. Therefore, propose that transition from adaptive maladaptive states, overload arises when added competes with longevity-promoting growth, maintenance, repair. Mechanistically, restriction maintenance repair progressive wear-and-tear molecular organ systems. proposed makes testable predictions around physiological, cellular, sub-cellular transduce mortality. We also highlight new avenues quantify its link health across lifespan, via integration systemic cellular measurements together classic biomarkers.

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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Mitochondrial diseases: from molecular mechanisms to therapeutic advances

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 9, 2025

Abstract Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism signaling. They possess various metabolic quality control mechanisms crucial maintaining normal activities. Mitochondrial genetic disorders can arise from a wide range mutations in either mitochondrial or nuclear DNA, which encode proteins other contents. These defects lead to breakdown metabolism, such the collapse oxidative phosphorylation, one mitochondria’s most critical functions. diseases, common group disorders, characterized by significant phenotypic heterogeneity. Clinical symptoms manifest systems organs throughout body, with differing degrees forms severity. The complexity relationship between mitochondria diseases results an inadequate understanding genotype-phenotype correlation these historically making diagnosis treatment challenging often leading unsatisfactory clinical outcomes. However, recent advancements research technology have significantly improved our management conditions. translations mitochondria-related therapies actively progressing. This review focuses on physiological mitochondria, pathogenesis potential diagnostic therapeutic applications. Additionally, this discusses future perspectives diseases.

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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Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging

Nature Aging, Год журнала: 2023, Номер 3(8), С. 1020 - 1035

Опубликована: Авг. 7, 2023

Abstract The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits multivariate genome-wide association study methods, we modeled their underlying genetic factor (‘mvAge’). mvAge (effective n = ~1.9 million participants European ancestry) identified 52 independent variants in 38 genomic loci. Twenty were novel (not reported input studies). Transcriptomic imputation age-relevant genes, VEGFA PHB1 . Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on ( P value 8.41 × 10 −5 ). Similarly, genetically proxied thiazolidinediones 3.50 −10 ), proprotein convertase subtilisin/kexin 9 inhibition 1.62 −6 angiopoietin-like protein 4, beta blockers calcium channel also had estimates. Extending the drug-target framework to 3,947 protein-coding prioritized 122 targets. Together, findings will inform future studies aimed at improving healthy aging.

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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Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

PLoS Biology, Год журнала: 2024, Номер 22(8), С. e3002723 - e3002723

Опубликована: Авг. 22, 2024

The transfer of mitochondrial DNA into the nuclear genomes eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated occur rare instances from one human generation next. Here, we investigated numtogenesis dynamics humans 2 ways. First, quantified Numts 1,187 postmortem brain blood samples different individuals. Compared circulating immune cells ( n = 389), postmitotic tissue 798) contained more Numts, consistent with their potential somatic accumulation. Within samples, observed a 5.5-fold enrichment Numt insertions dorsolateral prefrontal cortex (DLPFC) compared cerebellum suggesting that arose spontaneously during development or across lifespan. Moreover, an increase number was earlier mortality. brains individuals no cognitive impairment (NCI) who died at younger ages carried approximately per decade life lost than those lived longer. Second, tested dynamic using repeated-measures whole-genome sequencing design fibroblast model recapitulates several molecular hallmarks aging. These longitudinal experiments revealed gradual accumulation 1 every ~13 days. Numtogenesis independent large-scale genomic instability unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling impairing oxidative phosphorylation (OxPhos) only modestly increased rate numtogenesis, whereas patient-derived SURF1 -mutant exhibiting mtDNA accumulated 4.7-fold faster healthy donors. Combined, our data document spontaneous demonstrate association between cortical findings open possibility mito-nuclear horizontal gene among tissues produces functionally relevant over timescales shorter previously assumed.

Язык: Английский

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CheekAge: a next-generation buccal epigenetic aging clock associated with lifestyle and health

GeroScience, Год журнала: 2024, Номер 46(3), С. 3429 - 3443

Опубликована: Март 5, 2024

Abstract Epigenetic aging clocks are computational models that predict age using DNA methylation information. Initially, first-generation were developed to make predictions CpGs change with age. Over time, next-generation created relate both and health. Since existing constructed in blood, we sought develop a clock optimized for prediction cheek swabs, which non-invasive easy collect. To do this, collected MethylationEPIC data as well lifestyle health information from 8045 diverse adults. Using novel simulated annealing approach allowed us incorporate factors into training combination of CpG filtering, clustering, ensembling, CheekAge, an epigenetic has strong correlation age, displays high test–retest reproducibility across replicates, significantly associates plethora factors, such BMI, smoking status, alcohol intake. We validated CheekAge internal dataset multiple publicly available datasets, including samples patients progeria or meningioma. In addition exploring the underlying biology clock, provide free online tool allows users mine our methylomic

Язык: Английский

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