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FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction

ABSTRACT: Mitochondrial integrated stress response emerged as a major adaptive pathway to respiratory chain deficiency, but tissue-specifics of its regulation or how it adapts to different levels of mitochondrial dysfunction are largely unknown. Here we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Remarkably, although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of the mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue-specificity and dose-dependency of the mitoISR.

ORGANISM(S): Mus musculus

PROVIDER: GSE195947 | GEO | 2022/02/04

REPOSITORIES: GEO

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FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction

Project description:Mitochondrial integrated stress response emerged as a major adaptive pathway to respiratory chain deficiency, but tissue-specifics of its regulation or how it adapts to different levels of mitochondrial dysfunction are largely unknown. Here we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Remarkably, although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of the mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue-specificity and dose-dependency of the mitoISR.

2022-04-27 | PXD031324 | Pride

Mitochondrial myopathy elicits global starvation response through FGF21

Project description:Progressive mitochondrial respiratory chain (RC) deficiency is associated with a wide spectrum of adult-onset degenerative diseases, as well as with normal aging. We have previously generated the Deletor mice to model late-onset progressive RC defects. Here we report novel tissue-specific pathways contributing to mitochondrial disease pathogenesis, identified by gene expression analysis. We found that RC-deficient muscle fibers secrete the fasting-induced hormone, fibroblast growth factor 21 (FGF21). This response leads to fatty acid recruitment from adipocytes and resistance to high-fat-diet induced obesity in mice, but does not affect glucose or insulin metabolism. FGF21 is also induced in the muscle of mitochondrial myopathy patients and in other RC-deficient mice. These data show that skeletal muscle is an endocrine organ, which signals its energy deficiency through FGF21. Furthermore, RC deficiency in single muscle fibers initiates a global starvation response. These data have important implications for conditions with primary or secondary RC deficiency. Mice overexpressing mutant Twinkle (C10ORF2) protein are the first animal model for Progressive External Ophtalmoplegia (PEO). Using PEO-model and wt-mice, skeletal muscle (quadriceps femoris) was analyzed for gene expression profile.

2011-11-16 | E-GEOD-18119 | biostudies-arrayexpress

Mitochondrial myopathy elicits global starvation response through FGF21

2011-11-16 | GSE18119 | GEO

Muscle mitochondrial stress-induced metabolic adaptations do not require FGF21 action

Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions. Wildtype male mice and FGF21-knockout male mice, together with muscle specific UCP1-transgenic male animals, and double cross of FGF21-KO with UCP1-Tg male mice, were kept on a standardized low fat diet for 40 weeks. After sacrifice, subcutaneous white adipose tisseu (scWAT) was rapidly removed, weighed, and snap frozen in liquid nitrogen and used for RNA isolation and whole genome gene expression microarray hybridisation using Agilent arrays.

2016-01-07 | E-GEOD-71749 | biostudies-arrayexpress

Drosophila CNS mitochondrial DNA dysfunction microarray

Project description:Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level. We used microarray analysis to investigate gene expression in cases of mitochondrial dysfunction in the CNS. RNA was purified from the late third instar larval CNS from control larvae, or larvae over-expressing mitochondrial transcription factor A (TFAM) in post-mitotic neurons using the neuron specific driver nsyb-Gal4. Three replicates are included for each condition.

2013-12-20 | E-GEOD-53509 | biostudies-arrayexpress

Drosophila CNS mitochondrial DNA dysfunction microarray

Project description:Mitochondrial DNA (mtDNA) encodes essential components of the respiratory chain and loss of mtDNA leads to mitochondrial dysfunction and neurodegeneration. Mitochondrial transcription factor A (TFAM) is an essential component of mtDNA replication and a regulator of mitochondrial copy number in cells. Studies have shown that TFAM knockdown leads to mitochondrial dysfunction and respiratory chain deficiencies. ATP synthase is Complex V of the mitochondrial respiratory chain. It is driven by a proton gradient between the intermembrane space and the mitochondrial matrix and generates the majority of cellular ATP. The knockdown of coupling factor 6 (Cf6), one of the components of the proton channel F0, causes dysfunction in the complex, leading to mitochondrial dysfunction and respiratory chain deficiencies. Using gene expression analysis, we aimed to investigate the effects of mtDNA dysfunction in the CNS at the molecular level.

2013-12-20 | GSE53509 | GEO

Liver adapts mitochondrial function to insulin-resistant and diabetic states in mice

Project description:Objective: To study if diabetic and insulin-resistant states lead to mitochondrial dysfunction in the liver, or alternatively, if there is adaption of mitochondrial function to these states in the long-term range. Results: High-fat diet (HFD) caused insulin resistance and severe hepatic lipid accumulation, but respiratory chain parameters were unchanged. Livers from insulin-resistant IR/IRS-1+/- mice had normal lipid contents and normal respiratory chain parameters, however showed mitochondrial uncoupling. Livers from severely hyperglycemic and hypoinsulimic, streptozotocin (STZ)-treated mice had massively depleted lipid levels, but respiratory chain abundance was unchanged. However, their mitochondria showed increased abundance and activity of the respiratory chain, which was better coupled compared to controls. Conclusions: Insulin resistance, either induced by obesity or by genetic manipulation, does not cause mitochondrial dysfunction in the liver of mice. However, severe insulin deficiency and high blood glucose levels in mice cause an enhanced performance of the respiratory chain, probably in order to maintain the high energy requirement of the unsuppressed gluconeogenesis. We performed gene expression microarray analysis on liver tissue derived from mice treated with STZ or standard diet (control).

2013-12-10 | E-GEOD-39752 | biostudies-arrayexpress

FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction

Project description:FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction

| PRJNA802662 | ENA

Muscle mitochondrial stress-induced metabolic adaptations do not require FGF21 action

2016-01-07 | GSE71749 | GEO

Mitochondrial dysfunction remodels one-carbon metabolism in human cells

Project description:Bao XR, Ong SE, Goldberger O, Peng J, Sharma R, Thompson DA, Vafai SB, Cox A, Marutani E, Ichinose F, Goessling W, Regev A, Carr SA, Clish CB, Mootha VK. eLife 2016. Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mtDNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis.

2016-06-02 | MSV000079791 | MassIVE

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