High mitochondrial DNA content is a key determinant of stemness, proliferation, cell migration, and cancer metastasis in vivo DOI Creative Commons

Marta Mauro-Lizcano,

Filippo Di Pisa,

Luis Larrea Murillo

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(10)

Published: Oct. 11, 2024

Abstract Here, we examined the potential role of mitochondrial DNA (mtDNA) levels in conveying aggressive phenotypes cancer cells, using two widely-used breast cell lines as model systems (MCF7[ER+] and MDA-MB-231[ER-]). These human were fractionated into mtDNA-high mtDNA-low sub-populations by flow cytometry, SYBR Gold a vital probe to stain nucleoids living cells. Enrichment was independently validated, specific DNA-binding mAb (AC-30-10), mitochondrial-based functional assays. As predicted, MCF7 cells showed significant increases mass, membrane potential, superoxide production, well increased respiration ATP production. Moreover, demonstrated stemness features, such anchorage-independent growth CD44 levels, drug-resistance Gemcitabine Tamoxifen. Proliferation rates also significantly increased, with dramatic shift towards S- G2/M-phases cycle; this indeed confirmed RNA-Seq analysis. Complementary results obtained MDA-MB-231 More specifically, features rapid cycle progression. exhibited both migration invasion, suggesting for mtDNA distant metastasis. To test hypothesis more directly, preclinical vivo utilized. For purpose, tumour grafts treated an established synthesis inhibitor, namely Alovudine (3’-deoxy-3’-fluorothymidine). expected, drug-induced depletion led from glycolytic metabolism. Interestingly, very effectively reduced formation spontaneous metastases nearly 70%, but minimally inhibited approximately 20%. Taken together, these data suggest that high content is key driver stemness, proliferation, migration,

Language: Английский

The brain–body energy conservation model of aging DOI
Evan D. Shaulson, Alan A. Cohen, Martin Picard

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(10), P. 1354 - 1371

Published: Oct. 8, 2024

Language: Английский

Citations

7
Macrophage lysate-derived cytokine network combined with silk fibroin hydrogel promotes diabetic vascularized bone regeneration DOI Creative Commons
Muxin Yue,

Yong-sheng Zhou,

Zheng Li

et al.

Chemical Engineering Journal, Journal Year: 2024, Volume and Issue: 490, P. 151892 - 151892

Published: May 3, 2024

Cell-based therapies are used extensively in tissue engineering because of their great biosafety and diverse biological functions. Among them, macrophage lysate provides a comprehensive rich network cytokines to modulate the local immune microenvironment. However, effective strategies for lysate-based biomaterials with immune-regulatory function still lacking. In this study, we engineered silk fibroin hydrogel loaded THP-1 whole-cell regulate microenvironment promote vascularized bone regeneration diabetic defects. Specifically, by modulating expression pattern key enzyme energy metabolism (mitochondrial phosphoenolpyruvate carboxykinase, PCK2) cells, generated enriched anti-inflammatory factors. This facilitated osteogenic differentiation BMSCs angiogenesis HUVECs vitro, incorporating immunomodulatory into enhanced diabetes. Mechanistically, revealed that PCK2 activated nuclear factor-kappa B (NF-κB) signaling pathway macrophages using proteomic profiling. research new insights design cell-derived biomaterials, aiming improve therapeutic outcomes pathological

Language: Английский

Citations

5
A platform to map the mind–mitochondria connection and the hallmarks of psychobiology: the MiSBIE study DOI Creative Commons
Catherine Kelly, Caroline Trumpff,

Carlos Alberto Palacio Acosta

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(10), P. 884 - 901

Published: Oct. 1, 2024

Language: Английский

Citations

4
Large extracellular vesicles containing mitochondria (EVMs) derived from Alzheimer disease cells harbor pathologic functional and molecular profiles and spread mitochondrial dysfunctions DOI Open Access
Fanny Eysert, Véronique Legros, Anne-Sophie Gay

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

ABSTRACT In addition to small extracellular vesicles known as exosomes, cells release large containing mitochondria (EVMs). However, the molecular and functional characteristics of EVMs, well impact EVM secretion on spreading mitochondrial dysfunction between cells, remain unknown in context Alzheimer’s Disease (AD). Here, we provide an ultrastructural, biochemical, characterization EVMs isolated from expressing amyloid precursor protein (APP) with familial Swedish mutation (APPswe). We identified differential proteomic lipidomic signatures APPswe-derived compared control revealed a specific profile conditioned media fibroblasts AD patients at prodromal stage disease. Our findings show that APP-C terminal fragments (APP-CTFs) pathogenic accumulation potentiates through budding plasma membrane. lastly demonstrated APP-CTFs loaded are active carriers dysfunctional transfer pathology naïve recipient cells.

Language: Английский

Citations

0
Interaction and regulation of the mitochondrial proteome – in health and disease DOI Creative Commons
Johan Palmfeldt

Expert Review of Proteomics, Journal Year: 2025, Volume and Issue: 22(1), P. 19 - 33

Published: Jan. 2, 2025

Introduction Mitochondria contain multiple pathways including energy metabolism and several signaling synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases inherited metabolic disorders, complex common disorders like neurodegeneration, diabetes cancer, since they all to some degree have mitochondrial underpinnings.

Language: Английский

Citations

0
Genotype–Phenotype Correlation in Progressive External Ophthalmoplegia: Insights From a Retrospective Analysis DOI Open Access
J. Wang, Yan Lin,

Xingyu Zhuang

et al.

Neuropathology and Applied Neurobiology, Journal Year: 2025, Volume and Issue: 51(1)

Published: Jan. 17, 2025

ABSTRACT Background Progressive external ophthalmoplegia (PEO) is a classic manifestation of mitochondrial disease. However, the link between its genetic characteristics and clinical presentations remains poorly investigated. Methods We analysed clinical, pathological large cohort patients with PEO, based on type their mtDNA variations. Eighty‐two PEO were enrolled grouped into three categories: single large‐scale deletions (SLDs), multiple (MulDs) m.3243A > G point variant. Patients in SLD category further divided ‘common deletion’ ‘noncommon groups presence or absence 4977‐bp deletion. The mutational load deleted these was comprehensively detected by real‐time polymerase chain reaction (RT‐PCR). Results showed highest proportion cytochrome C oxidase‐negative (COX‐n) fibres muscle biopsy. exhibited an inverse relationship deletion length direct COX‐n fibre ratio. Compared having noncommon deletions, those common tend to have other involvement, lower body mass index (BMI) scores (17 ± 3 vs. 22 4 kg/m 2 ), higher (63% 22% 46% 24%), more (26% 9%, interquartile range [IQR]: 15%–32% 6%–26%) growth differentiation factor 15 (GDF15) levels (2583 1472, IQR: 1746–4081 924–2155 pg/mL). MulDs displayed milder symptoms, especially compared variant, as indicated later age onset (31 13, 27–49 6–29 years), BMI (24.0 16.5 3.4 lactate (1.6 1.1 6.3 6.0 mmol/L) ragged‐blue (RBFs) (3 16, 1%–9% 7%–27%). Conclusion variant group exhibits severe symptoms subgroups, particularly patients. In group, experience manifestations. These findings enhance our understanding facilitating diagnosis, prognosis counselling.

Language: Английский

Citations

0
Genetic Landscape and Mitochondrial Metabolic Dysregulation in Patients Suffering From Severe Long COVID DOI Creative Commons
Kristoffer Skaalum Hansen, Sofie E. Jørgensen, Cagla Cömert

et al.

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(3)

Published: March 1, 2025

ABSTRACT Long COVID represents a significant global health challenge with an unclear etiology. Alongside accumulating evidence of mitochondrial dysfunction in patients acute SARS‐CoV‐2 infection, symptomatic overlap exists between long and disorders. However, the genetic underpinnings have not been previously explored. We employed whole genome sequencing to analyze 13 severe identify defects related function. performed extracellular bioenergetics flux analysis on peripheral blood mononuclear cells proteomics evaluate cellular compared results those healthy controls. Our investigation identified 10 variants classified as pathogenic or likely 83 unknown significance affecting wide range mitochondria‐associated biological functions. Bioenergetics revealed altered ATP production rate four This study presents initial potential underlying predisposition while demonstrating energy capacity subset these patients. These findings open avenues for further research into role pathology suffering from may pave way targeted therapeutic strategies aimed at mitigating dysfunction.

Language: Английский

Citations

0
Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism DOI Creative Commons
KayLee K. Steiner, Arissa Young, Andrew R. Patterson

et al.

The Journal of Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Abstract Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These rely on distinct metabolic programs, modulation of which differentially affects fate function. Lipid metabolism is fundamental yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid genes pathways essential for functions. established mitochondrial fatty acid synthesis Mecr, Mcat, Oxsm as key regulators. Of these, the inborn error gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD8+ numbers, demonstrating that MECR not homeostatic conditions. However, memory cells were reduced knockout MECR-deficient proliferated, differentiated, survived less well than control cells. Interestingly, ultimately showed signs stress dysfunction absence MECR. Mecr-deficient also decreased respiration, tricarboxylic intermediates, accumulated intracellular iron, appeared contribute increased death sensitivity ferroptosis. Importantly, exhibited fitness disadvantages effective at driving disease an model bowel disease. Thus, MECR-mediated broadly supports proliferation survival vivo. findings may provide insight immunological state MECR- other synthesis–deficient patients.

Language: Английский

Citations

0
Assessing the role of mitonuclear interactions on mitochondrial function and organismal fitness in natural Drosophila populations DOI Creative Commons
Stefano Bettinazzi, Jane W. Liang, Enrique Rodríguez

et al.

Evolution Letters, Journal Year: 2024, Volume and Issue: 8(6), P. 916 - 926

Published: Aug. 9, 2024

Abstract Mitochondrial function depends on the effective interactions between proteins and RNA encoded by mitochondrial nuclear genomes. Evidence suggests that both genomes respond to thermal selection promote adaptation. However, contribution of their epistatic life history phenotypes in wild remains elusive. We investigated evolutionary implications mitonuclear a real-world scenario sees populations adapted different environments, altering geographical distribution while experiencing flow admixture. created Drosophila melanogaster panel with replicate native from ends Australian east-coast cline, into which we substituted mtDNA haplotypes were either predominant or rare at each cline-end, thus creating putatively matched mismatched populations. Our results suggest mismatching may impact phenotype, harboring rarer haplotype suffering trade-off aerobic capacity key fitness aspects such as reproduction, growth, survival. discuss significance modulators context future adaptation population persistence.

Language: Английский

Citations

3
APOE4 increases energy metabolism in APOE-isogenic iPSC-derived neurons DOI Creative Commons

Vanessa Budny,

Yannic Knöpfli,

Debora Meier

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Abstract The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower AD while APOE3 defined as neutral. APOE plays a prominent role in bioenergetic homeostasis of brain, and early-stage metabolic changes have been detected brains patients. Although primarily expressed by astrocytes neurons also shown source APOE. However, little about differential three isoforms neuronal energy homeostasis. this study, we generated pure human (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE-knockout (KO) investigate isoform-specific effects on metabolism. We showed that endogenously produced enhanced mitochondrial ATP production iN but not corresponding iPS cell line. This effect neither correlated with expression levels fission fusion proteins, nor intracellular secreted APOE, which were similar cells. basal respiration APOE-KO strongly differed more closely resembled indicating gain-of-function mechanism rather than loss-of-function. Taken together, our findings isogenic reveal genotype-dependent neuron-specific regulation oxidative

Language: Английский

Citations

2