Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis DOI Creative Commons
Sun Woo Sophie Kang,

Lauryn A. Brown,

Colin B. Miller

et al.

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

Published: Dec. 12, 2024

Abstract Hepatic lipid accumulation, or Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a significant risk factor for liver cancer. Despite the rising incidence of MASLD, underlying mechanisms steatosis and lipotoxicity remain poorly understood. Interestingly, accumulation also occurs during fasting, driven by mobilization adipose tissue-derived fatty acids into liver. However, how hepatocytes adapt to increased flux nutrient deprivation what differently in MASLD not known. To investigate differences handling response deficiency excess, we developed novel single-cell tissue imaging (scPhenomics) technique coupled with spatial proteomics. Our investigation revealed extensive remodeling droplet (LD) mitochondrial topology dietary conditions. Notably, fasted mice exhibited mitochondria-LD interactions, which were rarely observed Western Diet (WD)-fed mice. Spatial proteomics showed an increase PLIN5 expression, known mediator LD-mitochondria interaction, fasting. examine functional role interaction on handling, overexpressed variants. We found that phosphorylation state impacts its capacity form contact sites. S155A promoted organelle triglyceride (TG) synthesis, LD expansion fed control diet. Conversely, S155E expressing cells had fewer LDs sites contained less TG. Wild-type (WT) overexpression WD-fed reduced improved redox despite continued WD consumption. These findings highlight importance interactions metabolism, revealing critical mechanism maintain homeostasis metabolic stress. study underscores potential utility targeting therapeutic intervention.

Language: Английский

Rickettsia parkeri forms extensive, stable contacts with the rough endoplasmic reticulum DOI

Yamilex Acevedo‐Sánchez,

Patrick J. Woida, Caroline Anderson

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(3)

Published: Jan. 7, 2025

Upon invasion into the host cell, a subset of bacterial pathogens resides exclusively in cytosol. While previous research revealed how they reshape plasma membrane during invasion, subvert immune response, and hijack cytoskeletal dynamics to promote their motility, it was unclear if these also interacted with organelles this crowded intracellular space. Here, we examined obligate pathogen Rickettsia parkeri interacts endoplasmic reticulum (ER), large dynamic organelle spread throughout cell. Using live-cell microscopy transmission focused-ion-beam scanning electron microscopy, show that R. forms extensive contacts rough ER are ∼55 nm apart cover more than half surface. Depletion ER-specific tethers VAPA VAPB reduced rickettsia–ER contacts, were localized around rickettsiae. Overall, our findings illuminate an interkingdom contact uniquely mediated by rickettsiae mimics some characteristics traditional sites.

Language: Английский

Citations

1
Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos DOI Creative Commons
Yi Jiang, H. Wang, Kevin M. Boergens

et al.

Cell Reports Methods, Journal Year: 2025, Volume and Issue: 5(2), P. 100989 - 100989

Published: Feb. 1, 2025

Language: Английский

Citations

0
Three's company: Membrane waltz among organelles DOI
Valentin Guyard, Francesca Giordano

Biochimica et Biophysica Acta (BBA) - Bioenergetics, Journal Year: 2025, Volume and Issue: unknown, P. 149555 - 149555

Published: April 1, 2025

Language: Английский

Citations

0
Insulin resistance in type 2 diabetes mellitus DOI
Domenico Accili, Zhihui Deng, Qingli Liu

et al.

Nature Reviews Endocrinology, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Language: Английский

Citations

0
Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis DOI
Brandon Chen, Costas A. Lyssiotis, Yatrik M. Shah

et al.

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(8), P. 1487 - 1508

Published: April 1, 2025

Language: Английский

Citations

0
PPARα regulates ER–lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes DOI Creative Commons
Lauren F. Uchiyama, Alexander Nguyen, Kevin Qian

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(17)

Published: April 21, 2025

Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum–lipid droplet site protein, in the control of utilization adipose tissue. Here, we show that Clstn3b expression induced liver by nuclear receptor PPARα settings high utilization, including fasting ketogenic diet feeding. Hepatocyte-specific loss CLSTN3β mice impairs ketogenesis independent changes activation. Conversely, hepatic overexpression promotes mice. Mechanistically, affects LD–mitochondria crosstalk, as evidenced oxidation, lipid-dependent mitochondrial respiration, integrated stress response. These findings define function CLSTN3β-dependent membrane contacts ketogenesis.

Language: Английский

Citations

0
MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes DOI Creative Commons
Zer Vue,

Alexandria C. Murphy,

Han Le

et al.

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

Published: June 25, 2024

The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function increasing risk of systemic liver diseases. How three-dimensional (3D) structure changes in across biological mechanisms regulating such confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) achieve high-resolution 3D reconstructions murine mitochondria observe diverse phenotypes structural alterations that occur with age, marked by reduction size complexity. We also show concomitant metabolomic lipidomic aged samples. Aged human samples reflected altered disease risk. To find potential regulators change, examined Mitochondrial Contact Site Cristae Organizing System (MICOS) complex, which plays crucial role maintaining architecture. MICOS complex is lost during but not Sam50. Sam50 component sorting assembly machinery (SAM) acts tandem modulate cristae morphology. models subjected high-fat diet, there depletion protein SAM50. This expression may heighten susceptibility disease, as our biobank studies corroborate genetically regulated predisposition multiple further calcium dysregulation oxidative stress accompany disruption complex. Together, establish decrease complexity dysregulated metabolism aging. While these are partially be age-related loss confluence diet can cause Sam50, contributes summary, study reveals affect metabolism, targeted future therapeutic techniques.

Language: Английский

Citations

0
Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy DOI Creative Commons
Shuai Chen, Qinghe Zeng, Xiurong Cai

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(11), P. 4438 - 4457

Published: Jan. 1, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive that encompasses spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests dietary restriction (DR) sleeve gastrectomy (SG) can lead to remission hepatic steatosis inflammation through weight loss, but it unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims elucidate the intricate following DR, SG sham surgery rats fed high-fat diet as model obesity-related MASLD, comparison clinical cohort patients undergoing SG. Single-cell single-nuclei transcriptome analysis, spatial metabolomics, immunohistochemistry revealed landscape, while circulating biomarkers were measured serum samples. Artificial intelligence (AI)-assisted image analysis characterized distribution hepatocytes, myeloid cells lymphocytes. In experimental rats, improved body mass index, injury triglyceride levels. Both DR attenuated fibrosis rats. Metabolism-related genes (

Language: Английский

Citations

0
Efficient Cell-Wide Mapping of Mitochondria in Electron Microscopic Volumes Using webKnossos DOI
Yi Jiang, H. Wang, Kevin M. Boergens

et al.

Published: Jan. 1, 2024

Language: Английский

Citations

0
Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis DOI Creative Commons
Sun Woo Sophie Kang,

Lauryn A. Brown,

Colin B. Miller

et al.

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

Published: Dec. 12, 2024

Abstract Hepatic lipid accumulation, or Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a significant risk factor for liver cancer. Despite the rising incidence of MASLD, underlying mechanisms steatosis and lipotoxicity remain poorly understood. Interestingly, accumulation also occurs during fasting, driven by mobilization adipose tissue-derived fatty acids into liver. However, how hepatocytes adapt to increased flux nutrient deprivation what differently in MASLD not known. To investigate differences handling response deficiency excess, we developed novel single-cell tissue imaging (scPhenomics) technique coupled with spatial proteomics. Our investigation revealed extensive remodeling droplet (LD) mitochondrial topology dietary conditions. Notably, fasted mice exhibited mitochondria-LD interactions, which were rarely observed Western Diet (WD)-fed mice. Spatial proteomics showed an increase PLIN5 expression, known mediator LD-mitochondria interaction, fasting. examine functional role interaction on handling, overexpressed variants. We found that phosphorylation state impacts its capacity form contact sites. S155A promoted organelle triglyceride (TG) synthesis, LD expansion fed control diet. Conversely, S155E expressing cells had fewer LDs sites contained less TG. Wild-type (WT) overexpression WD-fed reduced improved redox despite continued WD consumption. These findings highlight importance interactions metabolism, revealing critical mechanism maintain homeostasis metabolic stress. study underscores potential utility targeting therapeutic intervention.

Language: Английский

Citations

0