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Mitochondrial reorganization is rate-limiting for direct cardiac reprogramming

ABSTRACT: Mitochondrial reorganization is rate-limiting for direct cardiac reprogramming

PROVIDER: PRJNA1120770 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29306153_1.fastq.gz	Fastqsanger.gz
	SRR29306153_2.fastq.gz	Fastqsanger.gz
	SRR29306154_1.fastq.gz	Fastqsanger.gz
	SRR29306154_2.fastq.gz	Fastqsanger.gz
	SRR29306155_1.fastq.gz	Fastqsanger.gz

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Mitochondrial reorganization is rate-limiting for direct cardiac reprogramming

Project description:Direct cardiac reprogramming of cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) has emerged as a promising potential therapeutic for preserving cardiac function after ischemic injury. Remaining barriers to clinical translation include low conversion efficiency and relative immaturity of iCMs. A major phenotypic distinction between CFs and native CMs is the latter’s reliance on mitochondrial energetics facilitated by their high mitochondrial fusion (joining) activity relative to fission (dividing) activity. However, how mitochondria reorganize during reprogramming remains understudied. We combined metabolic flux assays with novel microscopy techniques to characterize mitochondrial energetics and morphology over a time course of cardiac reprogramming with Mef2c, Gata4 and Tbx5 (MGT). We found that MGT reprogramming induces increased mitochondrial respiration and fusion. However, this reorganization occurs only at later reprogramming time points. Hypothesizing that mitochondrial reorganization represents a rate-limiting step in reprogramming, we then performed a loss of function screen for a panel of genes known to regulate mitochondrial morphology. We found that the fusion apparatus is essential for successful iCM conversion and identified the fission regulator Mtfr1l as a powerful barrier to reprogramming. Using transcriptomic analysis and concomitant knockdown of the Mtfr1l target Opa1, the effector of inner membrane fusion, we showed that loss of Mtfr1l dramatically improves reprogramming efficiency and the maturity of nascent iCMs by facilitating a metabolic switch toward more interconnected and energetically active mitochondria. This study represents a major step forward in understanding reprogramming mechanisms and is the first report of Mtfr1l as a significant barrier to iCM conversion and maturation.

2025-03-12 | GSE269231 | GEO

Identification of BBX proteins as rate-limiting co-factors of HY5

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Tcf21 functions as a rate-limiting factor during visceral adipose tissue development

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Project description:Quantifying RNA Synthesis at Rate-Limiting Steps of Transcription Using Nascent RNA-sequencing Data

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The role of PER1/2 and feeding rhythms in daily oscillations of mitochondrial nutrient utilization and rate-limiting enzymes

Project description:Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied mass-spectrometry based quantitative proteomics on isolated mitochondria from mice sacrificed throughout the day and identified extensive oscillations in the mitochondrial proteome. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or upon nutritional challenge such as high fat diet. We propose that the clock proteins PER1/2 optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby serve as a rheostat for mitochondrial nutrient utilization.

2018-10-17 | PXD001732 | Pride

Hierarchical RNA processing is rate limiting for mitochondrial ribosome assembly

Project description:In animals the organization of the compact mitochondrial genome and lack of introns have necessitated a unique mechanism for RNA processing. To date the regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. To understand the in vivo role of the endoribonuclease component of the RNase P complex, MRPP3, we created conditional knockout mice. Here we show that MRPP3 is essential for life, and heart and skeletal muscle-specific knockout leads to a cardiomyopathy early in life, indicating that it is the only RNase P enzyme in mitochondria. We show that RNA processing is required for the biogenesis of the respiratory chain and mitochondrial function. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-Seq enabled us to identify the in vivo cleavage sites of RNase P. Cleavage of the 5â² tRNA ends precedes 3â² end processing in vivo and is required for the correct biogenesis of the mitochondrial ribosomal subunits and mitoribosomal proteins that are differentially stabilized or degraded in the absence of mature rRNAs. Finally we identify that large mitoribosomal proteins can form a subcomplex on a precursor mt-RNA containing the 16S rRNA indicating that mitoribosomal biogenesis proceeds co-transcriptionally. Taken together our data show that RNA processing links transcription to translation via assembly of the mitoribosome. Total RNA was isolated from heart tissue from 11 week old control (Mrpp3loxP/loxP) and Mrpp3 knockout mice (Mrpp3loxP/loxP, +/Ckmm), TruSeq libraries produced in triplicate, sequenced and analysed for differential expression. Mitochondrial RNA was isolated from heart tissue from 11 week old control (Mrpp3loxP/loxP) and Mrpp3 knockout mice (Mrpp3loxP/loxP, +/Ckmm), PARE libraries produced in triplicate and sequenced for analysis of mitochondrial RNA processing.

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Project description:Tcf21 functions as a rate-limiting factor during visceral adipose tissue development [single-cell RNA-seq]

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Dbf4 recruitment by forkhead transcription factors defines an upstream rate-limiting step in determining replication origin firing

Project description:Initiation of eukaryotic chromosome replication follows a spatiotemporal program. Current model suggests that replication origins compete for a limited pool of initiation factors. However, it remains to be answered how these limiting factors are preferentially recruited to early origins. Here, we report that Dbf4 is enriched at early origins through its interaction with forkhead transcription factors Fkh1 and Fkh2. This interaction is mediated by Dbf4 C-terminus and was successfully reconstituted in vitro. An interaction defective mutant dbf4ΔC phenocopies fkh alleles in terms of origin firing. Remarkably, genome-wide replication profiles reveal that the direct fusion of the DNA-binding domain of Fkh1 to Dbf4 restores the Fkh-dependent origin firing, but specifically interferes with the pericentromeric origin activation. Furthermore, Dbf4 directly interacts with Sld3 and promotes the recruitment of downstream limiting factors. These data suggest that Fkh1 targets Dbf4 to a subset of non-centromeric origins to promote early replication, in a manner that is reminiscent to the recruitment of Dbf4 to pericentromeric origins by Ctf19.

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