Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance DOI Creative Commons
Laura Bierhansl, Lukas Gola,

Venu Narayanan

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(11), P. 9529 - 9538

Published: April 23, 2024

Abstract Epilepsy is one of the most common neurological disorders in world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent emergence seizures. However, up to a third patients suffer from drug-resistant epilepsy, there an urgent need develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics also might have effects on chronic epilepsy comorbidities such as cognitive decline depression. The mitochondrial calcium uniporter (MCU) mediates rapid Ca 2+ transport through inner membrane. influx essential for functions, but longer elevations intracellular levels are closely associated with seizure-induced neuronal damage, which underlying mechanisms Using neuronal-specific MCU knockout mice (MCU −/−ΔN ), we demonstrate deficiency reduced hippocampal excitability vivo. Furthermore, vitro analyses glioneuronal cells reveal no change total differences handling. reduces ROS production, declines metabolic fluxes, consequently prevents cell death. This effect was observed under pathological conditions, low magnesium culture model seizure-like activity excitotoxic glutamate stimulation, whereby suppresses overload seen WT cells. study highlights importance at interface handling metabolism mediator stress-related dysfunction, indicates modulation potential target future antiepileptogenic therapy.

Language: Английский

Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction DOI
Anna S. Monzel, José Antonio Enrı́quez, Martin Picard

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(4), P. 546 - 562

Published: April 26, 2023

Language: Английский

Citations

310
OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases DOI Creative Commons
Gabriel Sturm, Kalpita R. Karan, Anna S. Monzel

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Jan. 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.

Language: Английский

Citations

84
A practical guide for the analysis, standardization and interpretation of oxygen consumption measurements DOI
Ajit S. Divakaruni, Martin Jastroch

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(8), P. 978 - 994

Published: Aug. 15, 2022

Language: Английский

Citations

80
PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma DOI Creative Commons
Ligong Lu, Zhiling Zhou,

Xu-Yan Wang

et al.

Gut, Journal Year: 2022, Volume and Issue: 71(12), P. 2551 - 2560

Published: Feb. 16, 2022

Objective Patients with increased PD-L1 + host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim elucidate nature, regulation and functional relevance of hepatocellular carcinoma (HCC). Design A total untreated 184 HCC patients was enrolled randomly. C57BL/6 mice given injection Hepa1-6 form autologous hepatoma. ELISpot, flow cytometry real-time PCR applied analyse phenotypic characteristics isolated directly specimens paired blood samples or generated ex vivo vitro culture systems. Immunofluorescence immunohistochemistry performed detect presence immune on paraffin-embedded formalin-fixed samples. The regulatory mechanisms metabolic switching assessed by both studies. Results demonstrate that macrophages, which constructively represent major cellular source tumours, display an HLA-DR high CD86 glycolytic phenotype, significantly produce antitumourigenic IL-12p70 polarised intrinsic metabolism. Mechanistically, a key enzyme PKM2 triggered hepatoma cell derived fibronectin 1, via HIF-1α-dependent manner, concurrently controls properties inflammation-mediated expression macrophages. Importantly, although macrophages predict poor prognosis patients, blocking these eliminates PD-L1-dominant immunosuppression liberates properties. Conclusions Selectively modulating ‘context’ might restore their provide precise strategy for anticancer therapy.

Language: Английский

Citations

72
Metabolic regulation of the hallmarks of stem cell biology DOI Creative Commons
Benjamin T. Jackson, Lydia W.S. Finley

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(2), P. 161 - 180

Published: Feb. 1, 2024

Language: Английский

Citations

39
CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells DOI Creative Commons

Tyson J. Ruetz,

Angela N. Pogson, Chloe M. Kashiwagi

et al.

Nature, Journal Year: 2024, Volume and Issue: 634(8036), P. 1150 - 1159

Published: Oct. 2, 2024

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence proliferation in adult mammalian brain. Functional decline NSCs results decreased production new neurons and defective regeneration following injury during ageing

Language: Английский

Citations

22
Mitochondria in brain diseases: Bridging structural-mechanistic insights into precision-targeted therapies DOI Creative Commons
Jun Liao, Wenxiu He, Lisha Li

et al.

Published: Feb. 1, 2025

Language: Английский

Citations

4
Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers DOI Creative Commons
Rania El Botty,

Ludivine Morriset,

Élodie Montaudon

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 14, 2023

Abstract Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic metabolomics analyses of patients’ tumours, metastasis-derived patient-derived xenografts (PDX) isogenic cell lines we demonstrate that fraction metastatic ER BC highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth multiple palbociclib resistant PDX. Mutations PIK3CA / AKT1 genes are significantly associated response IACS-010759. At metabolic level, vivo decreased levels metabolites glutathione, glycogen pentose phosphate pathways treated tumours. In vitro, cells show increased dependency ROS upon treatment. Finally, patients, high expression predict poor prognosis. conclusion, these results identify as promising target for treatment patients.

Language: Английский

Citations

42
Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation DOI Creative Commons
Yeranuhi Hovhannisyan, Zhenlin Li, Domitille Callon

et al.

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Beyond the observed alterations in cellular structure and mitochondria, mechanisms linking rare genetic mutations to development of heart failure patients affected by desmin remain unclear due part, lack relevant human cardiomyocyte models.

Language: Английский

Citations

11
What can ATP content tell us about Barth syndrome muscle phenotypes? DOI Open Access
Jeffrey J. Brault, Simon J. Conway

Journal of Translational Genetics and Genomics, Journal Year: 2025, Volume and Issue: 9(1), P. 1 - 10

Published: Jan. 15, 2025

Adenosine triphosphate (ATP) is the energy currency within all living cells and involved in many vital biochemical reactions, including cell viability, metabolic status, death, intracellular signaling, DNA RNA synthesis, purinergic synaptic active transport, muscle contraction. Consequently, altered ATP production frequently viewed as a contributor to both disease pathogenesis subsequent progression of organ failure. Barth syndrome (BTHS) an X-linked mitochondrial characterized by fatigue, skeletal weakness, cardiomyopathy, neutropenia, growth delay due inherited TAFAZZIN enzyme mutations. BTHS widely hypothesized literature be model defective leading deficits. Prior patient data have linked impaired reduced phosphocreatine ratios (PCr/ATP) children adult hearts muscles, suggesting primary role for perturbed energetics. Moreover, although only limited direct measurements content ADP/ATP ratio (an indicator available from hydrolysis) so far been carried out, analysis divergent animal models, cultured types, diverse organs has failed uncover unifying understanding molecular mechanisms linking deficiency This review mainly focuses on energetics striated mitochondriopathy.

Language: Английский

Citations

2