Mitochondria at the crossroads of health and disease

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2601 - 2627

Published: May 1, 2024

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence life. How their structure function are dynamically tuned in response to tissue-specific needs for energy, growth repair, renewal is being increasingly understood. respond intrinsic extrinsic stresses can alter cell organismal by inducing metabolic signaling within cells distal tissues. Here, we review how centrality mitochondrial functions manifests health a broad spectrum diseases aging.

Language: Английский

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Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 24, 2024

Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of cellular composition early lesion. Here we present single cell resolution transcriptomics dataset acute infarction. Oligodendrocyte lineage cells and astrocytes range among most transcriptionally perturbed populations exhibit infarction- subtype-specific molecular signatures. Specifically, find infarction restricted proliferating oligodendrocyte precursor (OPCs), mature oligodendrocytes reactive astrocytes, exhibiting transcriptional commonalities in injury. OPCs are involved shared immuno-glial cross talk with stroke-specific myeloid cells. Within perilesional zone, osteopontin positive accumulate close proximity CD44

Language: Английский

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Primary cilia sense glutamine availability and respond via asparagine synthetase

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(3), P. 385 - 397

Published: March 6, 2023

Abstract Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable integrating multiple signalling cues, but their precise sensory function not fully understood. Here we show that primary respond to nutrient availability adjust length via glutamine-mediated anaplerosis facilitated asparagine synthetase (ASNS). Nutrient deprivation causes elongation, mediated reduced mitochondrial function, ATP AMPK activation independently mTORC1. Of note, glutamine removal replenishment necessary sufficient induce ciliary elongation or retraction, respectively, under stress conditions both in vivo vitro restoring ASNS-dependent glutamate generation. Ift88-mutant lacking glutamine-dependent during stress, due expression activity ASNS base cilia. Our data indicate a role for responding to, possibly sensing, cellular levels stress.

Language: Английский

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Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 5, 2024

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation gradually compartmentalized and restricted to specific tissue niches such as lesion rim. However, precise cell type composition niches, their interactions changes between active inactive stages are incompletely understood. We used single-nucleus spatial transcriptomics from subcortical MS corresponding control tissues map types associated pathways nonlesion areas. identified perivascular spaces, inflamed rim or core that with glial scar cilia-forming astrocyte subtype. Focusing on lesions, we uncovered cell–cell communication events myeloid, endothelial types. Our results provide insight into cellular composition, multicellular programs intercellular in along conversion homeostatic dysfunctional state underlying progression MS. Lerma-Martin et al. generated paired RNA sequencing dataset multiple identifying key driving inflammation at

Language: Английский

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NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(9)

Published: May 20, 2024

Ciliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant cilia, and its dysregulation may contribute to ciliopathies neurodegeneration. Mutation of deglutamylase CCP1 causes infantile-onset In C. elegans, ccpp-1 loss age-related degradation that suppressed a mutation conserved NEK10 homolog nekl-4. NEKL-4 absent from yet it negatively regulates stability via an unknown, glutamylation-independent mechanism. We show was mitochondria-associated. Additionally, nekl-4 mutants had longer mitochondria, higher baseline mitochondrial oxidation state, ccpp-1∆ mutant lifespan extension response oxidative stress. A kinase-dead nekl-4(KD) ectopically localized cilia rescued degenerating doublet B-tubules. nondegradable nekl-4(PEST∆) resembled with dye-filling B-tubule breaks. The Dyf phenotype depolymerizing kinesin-8 KLP-13/KIF19A. conclude influences activating kinesins promoting homeostasis.

Language: Английский

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Bridging lipid metabolism and mitochondrial genome maintenance

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(8), P. 107498 - 107498

Published: June 27, 2024

Language: Английский

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Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: April 9, 2022

Abstract The lack of understanding the cellular and molecular basis clinical genetic heterogeneity in progressive multiple sclerosis (MS) has hindered search for new effective therapies. Here, to address this gap, we analysed 632,000 single nuclei RNAseq profiles 156 brain tissue samples, comprising white matter (WM) lesions, normal appearing WM, grey (GM) lesions GM from 54 MS patients 26 controls. We observed expected changes overall neuronal glial numbers previously described within classical lesion subtypes. found highly cell type-specific gene expression tissue, with distinct differences between WM areas, confirming different pathologies. However, surprisingly, did not observe signatures types, rather a continuum change. This indicates that characterization better reflects abundance than type expression, global disease effect. Furthermore, major biological determinants variability samples relate individual patient effects, types or other metadata. identify four subgroups patterns oligodendrocyte stress and/or maturation, suggestive engagement pathological processes, an additional more variable regenerative astrocyte signature. discovery these patterns, which were also independent cohort, provides framework use biomarkers stratify optimal therapeutic approaches MS, significantly advances our mechanistic highlights need precision-medicine among patients.

Language: Английский

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Primary cilia shape hallmarks of health and aging

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 567 - 579

Published: May 1, 2023

Language: Английский

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Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14421 - 14421

Published: Sept. 22, 2023

Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which a well-accepted event in pathogenesis of Several common mechanisms are shared by genetically or pathologically distinct diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding translational dysfunction, autophagy activation. Progressive loss neuronal population due increased stress leads mostly accumulation dysfunctional mitochondria. Mitochondrial dysfunction excessive neuroinflammatory responses both sufficient induce pathology neurodegeneration. Therefore, quality control key determinant health survival cells brain. Research has been primarily focused demonstrate significance health, despite important contributions non-neuronal constitute significant portion brain volume. Moreover, morphology function distinctly diverse different tissues; however, little known about their molecular diversity among cell types. dynamics types markedly decide fate overall health; therefore, it not justifiable overlook active contribution facilitating health. In this review article, we aim discuss how remarkable highly synchronized connecting property keeping neurons healthy

Language: Английский

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Keeping pace: the primary cilium as the conducting baton of the islet

Diabetologia, Journal Year: 2024, Volume and Issue: 67(5), P. 773 - 782

Published: Feb. 14, 2024

Abstract Primary cilia are rod-like sensory organelles that protrude from the surface of most mammalian cells, including cells islet, and mounting evidence supports important roles these structures in regulation beta cell function insulin secretion. The abilities cilium arise local receptor activation is coupled to intrinsic signal transduction, ciliary signals can propagate into influence function. Here, we review recent advances studies provide insights intra-islet cues trigger primary signalling; how second messenger generated propagated within cilia; signalling affects We also discuss potential involvement development progression type 2 diabetes, identify gaps our current understanding islet suggestions on further this intriguing structure. Graphical

Language: Английский

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