FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction
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ABSTRACT:
PROVIDER: PRJNA802662 | ENA |
REPOSITORIES: ENA
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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.
2022-02-04 | GSE195947 | GEO
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
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
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
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.
2016-01-07 | GSE71749 | GEO
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.
2011-11-16 | GSE18119 | GEO
Project description:FGF21 belongs to the FGF superfamily and the highest expression of the FGF21 transcript was found in the liver. The initial studies identified FGF21 as an endocrine hepatokine with crucial roles in regulating lipid, glucose and energy metabolism. More recent studies have indicated a role for FGF21 in cardiovascular stress and diseases.The goal of our study is to analyze the effect of FGF21 on ischemic cardiomyocytes transcriptome using microarray. Total RNA was extracted from cultured neonatal mice cardiomyocytes after exposure to hypoxia (in 2% oxygen, 5% CO2 and 93% N2) for 12 h in the absence or presence of FGF21. Samples were processed for hybridization to the Mouse Gene 2.0 ST Array (Affymetrix). We sought to find out the differentially expressed genes regulated by FGF21 in hypoxic cardiomyocytes.
2016-04-13 | E-GEOD-80199 | biostudies-arrayexpress
Project description:FGF21 belongs to the FGF superfamily and the highest expression of the FGF21 transcript was found in the liver. The initial studies identified FGF21 as an endocrine hepatokine with crucial roles in regulating lipid, glucose and energy metabolism. More recent studies have indicated a role for FGF21 in cardiovascular stress and diseases.The goal of our study is to analyze the effect of FGF21 on ischemic cardiomyocytes transcriptome using microarray.
2016-04-13 | GSE80199 | GEO
Project description:Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand proteins encoded by nuclear genome. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 targets methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), the rate-limiting enzyme for nuclear NAD+ synthesis. Hepatic LSD1 knockout reduces NAD+-dependent Sirt1 and Sirt7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABP and PGC-1, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
2021-02-01 | GSE145089 | GEO
Project description:During early post-natal stage, cardiomyocytes undergo dramatic structural, metabolic, electrophysiological and cell cycle alterations towards maturation. Among them, the metabolic shift from carbohydrates to fatty acids metabolism is achieved along with mitochondrial biogenesis, dynamic switch and mitophagy. However, the regulatory mechanisms responsible for coordinated mitochondrial dynamics and mitophagy in mitochondrial maturation remain unclear. Here, we found that ablation of PDK1 in post-natal cardiomyocytes impairs mitochondrial maturation and metabolism, characterizing by arrest of mitochondria in neonatal stage, low levels of a subset of fatty acids and acylcarnitines. In addition, loss of PDK1 results in dysregulated mitochondrial dynamics and mitophagy. An imbalance of the AMPK-mTOR pathway and reduced phosphorylation of PDK1 substrates, including PKA and PKC family members, are observed. These results demonstrated that PDK1 ensures mitochondrial maturation and metabolic shift through kinase-dependent substrate phosphorylation and maintenance of the AMPK-mTOR axis to coordinate mitochondrial dynamics and mitophagy.
2023-08-01 | GSE215056 | GEO