Quantitative analyses of structure-function heterogeneity of individual mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplastic transformation DOI Open Access

Mayank Saini,

Swati Agarwala,

Biratal Wagle

et al.

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

Published: Dec. 26, 2024

Abstract Quantitative understanding of mitochondrial heterogeneity is necessary for elucidating the precise role these multifaceted organelles in tumor cell development. We demonstrate an early mechanistic mitochondria initiating neoplasticity by performing quantitative analyses structure-function single components coupled with transcriptomics. that large Hyperfused-Mitochondrial-Networks (HMNs) keratinocytes promptly get converted to heterogenous Small-Mitochondrial-Networks (SMNs) as stem enriching dose model carcinogen, TCDD, depolarizes mitochondria. This happens physical reorganization HMN nodes and edges, which enriches redox tuned SMNs distinct network complexity. leads establishment transcriptomic interaction between upregulated relevant mtDNA genes lineage specific stemness gene, KRT15, prior cycle exit. The SMN enrichment related connections are sustained neoplastic population. Consistently, carcinogenic incapable causing pronounced fails establish its linked mtDNA-KRT15(stemness) mtDNA-KRT15 modulation confirmed cSCC tumors, while highlighting patient heterogeneity. Therefore, we propose redox-tuned primes transformation establishing mtDNA-stemness exit towards specifying quiescent cells. Our data implies SMNs, created fission, would be tuning balance fission-fusion during transformation. proposed cancer etiology potentially designing precision strategies prevention therapy. Significance Statement challenges complex cellular organelles, mitochondria, can overcome their analyses. use a combinatorial approach single-mitochondrial-components scRNA-seq elucidate mechanism priming initiation carcinogen. conversion non-transformed Mechanistically, enriched edges networks, tunes interactions state stemness. Further probing our fundamental findings light may facilitate refinement various based targeted therapies.

Language: Английский

Dynamic GelMA/DNA Dual‐Network Hydrogels Promote Woven Bone Organoid Formation and Enhance Bone Regeneration DOI Open Access
Mengchun Zhu, Hao Zhang,

Qirong Zhou

et al.

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

Abstract Bone organoids, in vitro models mimicking native bone structure and function, rely on 3D stem cell culture for self‐organization, differentiation, ECM secretion, biomineralization, ultimately forming mineralized collagen hierarchies. However, their development is often limited by the lack of suitable matrices with optimal mechanical properties sustained growth differentiation. To address this, a dynamic DNA/Gelatin methacryloyl (GelMA) hydrogel (CGDE) developed to recapitulate key biochemical features ECM, providing supportive microenvironment organoid formation. This dual‐network engineered through hydrogen bonding between DNA GelMA, combined GelMA network crosslinking, resulting appropriate strength enhanced viscoelasticity. During 21‐day culture, CGDE facilitates cellular migration promoting woven (WBO) formation via intramembranous ossification. These WBOs exhibit spatiotemporal architectures supporting mineralization tissue remodeling. In vivo studies demonstrate that CGDE‐derived self‐adaptive properties, enabling rapid osseointegration within 4 weeks. work highlights as robust scalable platform development, offering new insights into biology innovative strategies regeneration.

Language: Английский

Citations

5
The Potential Role of Mitochondria in the Microbiota-Gut-Brain Axis: Implications for Brain Health DOI Creative Commons
Lei Qiao, Ge Yang, Peng Wang

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 209, P. 107434 - 107434

Published: Sept. 25, 2024

Mitochondria are crucial organelles that regulate cellular energy metabolism, calcium homeostasis, and oxidative stress responses, playing pivotal roles in brain development neurodegeneration. Concurrently, the gut microbiota has emerged as a key modulator of physiology pathology through microbiota-gut-brain axis. Recent evidence suggests an intricate crosstalk between mitochondrial function, mediated by microbial metabolites can influence activities brain. This review aims to provide comprehensive overview emerging role mitochondria critical mediators axis, shaping health neurological disease pathogenesis. We discuss how such short-chain fatty acids, secondary bile tryptophan metabolites, trimethylamine N-oxide traverse blood-brain barrier modulate processes including production, regulation, mitophagy, neurons glial cells. Additionally, we proposed targeting diet, prebiotics, probiotics, or promising potential therapeutic approach maintain optimizing fitness. Overall, further investigations into its bioenergetics, dynamics, responses will valuable insights axis both states.

Language: Английский

Citations

14
Compositionally unique mitochondria in filopodia support cellular migration DOI
Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen

et al.

Current Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

2
Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus DOI Creative Commons

Yansi Xian,

Bin Liu, Tao Shen

et al.

Bone Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: March 3, 2025

Abstract Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 T2DM. Decreased expression impaired mitochondrial quality control mechanism are observed both vitro vivo models Mechanistically, suppression results hyperacetylation FOXO3, hindering activation PINK1/PRKN mediated mitophagy pathway resulting accumulation dysfunctional mitochondria. Genetical overexpression or pharmacological restores deacetylation status thus facilitating ameliorating osteogenic impairment Collectively, our findings highlight fundamental regulatory control, crucial for maintaining homeostasis These insights not only enhance understanding molecular mechanisms underlying diabetic osteoporosis but also identify as promising therapeutic target osteoporosis.

Language: Английский

Citations

2
Single-cell atlas reveals multi-faced responses of losartan on tubular mitochondria in diabetic kidney disease DOI Creative Commons
Zhen Zhu, Guangxin Luan, Song Wu

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 21, 2025

Mitochondria are crucial to the function of renal tubular cells, and their dynamic perturbation in many aspects is an important mechanism diabetic kidney disease (DKD). Single-nucleus RNA sequencing (snRNA-seq) technology a high-throughput analysis technique for at level single cell nucleus. Here, our DKD mouse single-cell conveys more comprehensive mitochondrial profile, which helps us further understand therapeutic response this unique organelle family drugs. After high fat diet (HFD), mice were intraperitoneally injected with streptozotocin (STZ) induce DKD, then divided into three subsets: CON (healthy) subset, (vehicle) LST (losartan; 25 mg/kg/day) subset. Divide HK-2 LG (low glucose; 5 mM) HG (high 30 + 1 µ M) subsets. snRNA-seq was performed on tissues subset mice. To reveal effects losartan gene pathway changes mitochondria, Gene Ontology (GO) enrichment GSEA/GSVA scoring analyze specific proximal (PT) mitochondria treatment, including key events homeostasis such as morphology, dynamics, mitophagy, autophagic flux, respiratory chain, apoptosis, ROS generation. Preliminary validation through vitro vivo experiments, observation morphology dynamics using probes Mitotracker Red, evaluation effect electron microscopy, laser confocal immunofluorescence, Western blotting. Detection flux cells by transfecting Ad-mCherry-GFP-LC3B dual fluorescence labeled adenovirus. Various fluorescent energy detector used detect ROS, respiration mitochondrion. Through atlas kidneys, it found that treatment significantly increased percentage PT cells. differentially expressed genes showed autophagy mitochondrion pathway. Further GSEA GSVA revealed mitophagy other events, production, membrane potential, adenosine triphosphate (ATP) synthesis, involved protective thereby improving homeostasis. Consistent results also obtained cellular experiments. In addition, we highlighted subpopulation phenotype data, preliminarily validated co-localization expression Pink1 Gclc specimens patients treated losartan. Our research suggests scRNA-seq can reflect multifaceted landscape after drug these findings may provide new targets therapy level.

Language: Английский

Citations

1
SLC25A48 controls mitochondrial choline import and metabolism DOI Creative Commons
Anthony R.P. Verkerke, Xu Shi, Mark Li

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 2156 - 2166.e9

Published: Aug. 6, 2024

Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, underlying mechanisms biological significance remain poorly understood. Here, we report that SLC25A48, previously uncharacterized mitochondrial inner-membrane carrier protein, controls choline transport synthesis choline-derived methyl donors. We found SLC25A48 was required brown fat thermogenesis, respiration, membrane integrity. uptake matrix via facilitated betaine purine nucleotides, whereas loss resulted in increased production reactive oxygen species imbalanced lipids. Notably, human cells carrying single nucleotide polymorphism on gene cancer lacking exhibited decreased import, oxidative stress, impaired cell proliferation. Together, this study demonstrates regulates catabolism, bioenergetics, survival.

Language: Английский

Citations

4
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity DOI Creative Commons
Anna S. Monzel,

Jack Devine,

Darshana Kapri

et al.

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

Published: Feb. 4, 2025

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions. All mitochondria share general features, but not all created equal.Here we develop quantitative pipeline define the degree molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds validated genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0) simple mitotyping allows investigators quantify and interpret diversity plasticity from transcriptomics data across variety natural experimental contexts. We show mouse human multi-organ mitotypes segregate along two main axes specialization, contrasting anabolic (liver) catabolic (brain) tissues. In brain, cell-type-specific enrichment at single cell level. cultured primary fibroblasts exhibiting robust time-dependent treatment-induced metabolic plasticity, demonstrate how mitotype given type recalibrates i) over time in parallel with hallmarks aging, ii) response genetic, pharmacological, perturbations. Investigators can now use MitotypeExplorer.org associated code visualize, multivariate space biology.

Language: Английский

Citations

0
Ratiometric core/shell Nanosensors for Simultaneously Measuring Mitochondrial ATP Production and Oxygen Consumption in Living Cells DOI

Rui Jiang,

Ying Lian,

Enlai Yang

et al.

Phenomics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Language: Английский

Citations

0
Engineered tantalum sulfide nanosheets for effective acute liver injury treatment by regulating oxidative stress and inflammation DOI
Wang Qi, Tianjiao Zhao, Min Liu

et al.

Journal of Colloid and Interface Science, Journal Year: 2025, Volume and Issue: unknown, P. 137596 - 137596

Published: April 1, 2025

Language: Английский

Citations

0
Neuroadaptation in neurodegenerative diseases: compensatory mechanisms and therapeutic approaches DOI

Spandana Rajendra Kopalli,

Tapan Behl, Lalji Baldaniya

et al.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Journal Year: 2025, Volume and Issue: 139, P. 111375 - 111375

Published: April 23, 2025

Language: Английский

Citations

0