Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria
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ABSTRACT:
PROVIDER: PRJNA433399 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6683840.fastq.gz | Fastqsanger.gz | |||
| SRR6683841.fastq.gz | Fastqsanger.gz | |||
| SRR6683842.fastq.gz | Fastqsanger.gz | |||
| SRR6683843.fastq.gz | Fastqsanger.gz | |||
| SRR6683844.fastq.gz | Fastqsanger.gz |
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Project description:Here we show that synthesis of the mitochondrial phospholipid cardiolipin is an indispensable driver of thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response by overexpressing cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency diminishes mitochondrial uncoupling in brown and beige adipocytes and elicits a nuclear transcriptional response through ER stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake and renders animals strikingly insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin is a powerful regulator of organismal energy homeostasis through thermogenic fat bioenergetics.
2018-07-19 | GSE110297 | GEO
Project description:Adaptive thermogenesis has attracted much attention because of its ability to raise systemic energy expenditure and counter obesity and diabetes. Recent data have indicated that thermogenic fat cells utilize creatine to stimulate futile substrate cycling, dissipating chemical energy as heat. This model was based on the super-stoichiometric relationship between creatine added to mitochondria and O2 consumed, and this project aims at providing direct evidence for the molecular basis of this futile creatine cycling activity. In this project, we found that thermogenic fat cells contain robust phosphocreatine hydrolase (PCr’ase) activity, attributable to tissue-nonspecific alkaline phosphatase (TNAP), which was identified by the quantitative mass spectrometric analysis of a purified mitochondrial protein fraction containing the PCr’ase activity. TNAP hydrolyzes phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation; it is localized to mitochondria of thermogenic fat cells, where the futile creatine cycling occurs. Furthermore, we demonstrated in this project the essential role of TNAP in activating the futile creatine cycling and increasing whole body energy expenditure using genetic and pharmacological approaches. We also found that the genetic depletion of TNAP in murine adipose tissue causes rapid-onset obesity, with no change in movement or feeding behavior of the animals. Using quantitative mass spectrometry, we showed that genetic depletion of TNAP causes an upregulation of UCP1, as well as other proteins involved in oxidative metabolism, to compensate for a dampened thermogenesis. In summary, the data we acquired in this project illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycling and adipose thermogenesis.
2022-02-17 | PXD025032 | Pride
Project description:Mitochondria are the energy-generating hubs of the cell. In spite of considerable advances, our understanding of the factors that regulate the molecular circuits that govern mitochondrial function remains incomplete. Using a genome-wide functional screen, we have identified the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) as regulator of mitochondrial physiology. We show that Zc3h10 is a nuclear RNA binding protein that controls the fate of Slc25a37 and Prelid3a mRNA transcripts, two nuclear-encoded mitochondrial proteins central for iron and cardiolipin homeostasis. Depletion of Zc3h10 results in mitochondrial dysfunction and reduced TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with decreased mitochondrial function, increased body mass index, fat mass, fasting glucose and triglycerides. Cells from Cys105 homozygotes display alterations in Slc25a37 and Prelid3a levels and defects in mitochondrial iron and cardiolipin homeostasis that derive in mitochondrial dysfunction.
2023-05-22 | GSE99138 | GEO
Project description:Mitochondria are the energy-generating hubs of the cell. In spite of considerable advances, our understanding of the factors that regulate the molecular circuits that govern mitochondrial function remains incomplete. Using a genome-wide functional screen, we have identified the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) as regulator of mitochondrial physiology. We show that Zc3h10 is a nuclear RNA binding protein that controls the fate of Slc25a37 and Prelid3a mRNA transcripts, two nuclear-encoded mitochondrial proteins central for iron and cardiolipin homeostasis. Depletion of Zc3h10 results in mitochondrial dysfunction and reduced TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with decreased mitochondrial function, increased body mass index, fat mass, fasting glucose and triglycerides. Cells from Cys105 homozygotes display alterations in Slc25a37 and Prelid3a levels and defects in mitochondrial iron and cardiolipin homeostasis that derive in mitochondrial dysfunction.
2023-05-22 | GSE99137 | GEO
Project description:Mitochondria are the energy-generating hubs of the cell. In spite of considerable advances, our understanding of the factors that regulate the molecular circuits that govern mitochondrial function remains incomplete. Using a genome-wide functional screen, we have identified the poorly characterized protein Zinc finger CCCH-type containing 10 (Zc3h10) as regulator of mitochondrial physiology. We show that Zc3h10 is a nuclear RNA binding protein that controls the fate of Slc25a37 and Prelid3a mRNA transcripts, two nuclear-encoded mitochondrial proteins central for iron and cardiolipin homeostasis. Depletion of Zc3h10 results in mitochondrial dysfunction and reduced TCA cycle flux. Notably, we have identified a loss-of-function mutation of Zc3h10 in humans (Tyr105 to Cys105) that is associated with decreased mitochondrial function, increased body mass index, fat mass, fasting glucose and triglycerides. Cells from Cys105 homozygotes display alterations in Slc25a37 and Prelid3a levels and defects in mitochondrial iron and cardiolipin homeostasis that derive in mitochondrial dysfunction.
2023-05-22 | GSE99136 | GEO
Project description:Traditional ideas hold that the accumulation of mitochondria in thermogenic adipose tissue, namely brown and beige fat, helps to increase energy expenditure (EE), thereby alleviating obesity and metabolic disorders. However, recent studies in mice have shown that knocking out key proteins that maintain mitochondrial function can inhibit the activation of thermogenic fat while somehow protecting the mice from high-fat diet (HFD)–induced metabolic disorders. Therefore, the specific role of adipose mitochondria in metabolic benefits needs further analysis. Here, our use of non-biased sequencing-based screening identified YY1 as a key player in maintaining mitochondrial function in thermogenic adipose tissue. YY1 promotes the transcription of electron transport chain (ETC) genes during thermogenesis; thus, YY1 adipose knockout (YAKO) mice showed reduced body temperature and EE under cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced obesity and insulin resistance, which can be attributed to a repression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 in adipocytes directs glucose metabolism toward lactate, enhances the uptake of glutamine, and promotes the production of anti-inflammatory spermidine. Blocking spermidine production can reverse the beneficial metabolic effects observed in YAKO mice. In summary, our findings reveal a metabolic reprogramming pathway centered on adipose mitochondria; that is, although blocking YY1 reduced the mitochondria content, it generated spermidine and alleviated adipose inflammation, therefore leads to a thermogenic capacity-metabolic benefits uncoupling phenomenon.
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Project description:Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin-remodeling, upon loss of the cardiolipin acyl transferase Tafazzin, mutes HIF-1a signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1a regulation but rather HIF-1a gene-expression, a dysfunction recapitulated in iPSCs-derived cardiomyocytes from Barth Syndrome patients with Tafazzin-deficiency. RNAseq analyses confirmed drastically altered signaling in Tafazzin mutant cells. In hypoxia, Tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-kB activation and concomitantly HIF-1a gene-expression. In agreement, Tafazzin-deficient mice hearts display reduced HIF-1a levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1a signaling through inactivation of a non-canonical signaling pathway: Lack of NF-kB activation through reduced mitochondrial ROS production diminishes HIF-1a transcription.
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Project description:Analysis of the transcriptome of cardiac tissue from mice transgenically expressing human cardiolipin synthesis. The hypothesis tested was that cardiac specific transgenic expression of cardiolipin synthase alters myocardial lipidomic flux resulting in compensatory metabolic gene transcriptional changes that will attenuate pathological environmental and dietary insults on bioenergetics. Total RNA obtained from cardiac tissue from transgenic cardiac specific expressing human cardiolipin synthase 1 (hCLS1) mouse model at 4 months of age compared to wildtype littermates
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Project description:Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and -adrenergic signaling, but here we report that cold temperature can directly activate a thermogenic gene program in adipocytes independent of -adrenergic signaling.
2018-08-16 | E-MTAB-4526 | biostudies-arrayexpress
Project description:The activity of brown fat, a tissue mediating non-shivering thermogenesis, is associated with protection against obesity, diabetes, and cardiovascular disease. In response to thermogenic stimuli, brown adipose tissue (BAT) increases its activity through extensive cellular and tissue plasticity. While macroautophagy is typically inhibited during BAT thermogenic activation, we found that chaperone-mediated autophagy (CMA), a selective type of autophagy, is instead induced. CMA induction enhances both basal and cAMP-stimulated activity of brown adipocytes, as evidenced by increased expression of thermogenesis-related genes, enhanced release of brown adipokines, elevated cellular oxidative activity, and increased lipolysis. In aging, when BAT activity declines, LAMP2A—the limiting CMA component—is downregulated in BAT. However, pharmacological activation of CMA restores BAT activity in aged mice. To investigate the consequences of this CMA failure in BAT, we generated brown adipocytes knock down for LAMP2A and using comparative proteomics identified that CMA regulates levels of proteins involved in BAT thermogenic and metabolic activity. We demonstrate that selective CMA blockade in interscapular BAT in mice leads to reduced energy expenditure, increased triglyceridemia, lower expression of thermogenic markers and BAT-secretory functions, and to accumulation of thermogenesis repressors upon thermogenic activation. Overall, these findings support the essential role of CMA in BAT function and adaptation to thermogenic activation. CMA facilitates the timely degradation of thermogenic repressors, thereby promoting adaptive enhancement of thermogenic activity.
2025-09-30 | PXD062807 | Pride