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Dynamin-related protein 1 regulates substrate oxidation in skeletal muscle by stabilizing cellular and mitochondrial calcium dynamics

ABSTRACT: Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulators of mitochondrial dynamics play a causative role in nutrient regulation remains unclear. In this study, we generated a cellular loss-of-function model for dynamin-related protein 1 (DRP1), the primary regulator of outer membrane mitochondrial fission. Loss of DRP1 (shDRP1) resulted in extensive ultrastructural and functional remodeling of mitochondria, characterized by pleomorphic enlargement, increased electron density of the matrix, and defective NADH and succinate oxidation. Despite increased mitochondrial size and volume, shDRP1 cells exhibited reduced cellular glucose uptake and mitochondrial fatty acid oxidation. Untargeted transcriptomic profiling revealed severe downregulation of genes required for cellular and mitochondrial calcium homeostasis, inhibition of ATP-stimulated calcium flux, and impaired substrate oxidation stimulated by calcium levels. The insights obtained herein suggest that DRP1 regulates fatty acid oxidation by altering whole-cell and mitochondrial calcium dynamics. These findings are relevant to the targetability of mitochondrial fission and have clinical relevance in the identification of treatments for fission-related pathologies such as hereditary neuropathies, inborn errors in metabolism, cancer, and chronic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE162983 | GEO | 2021/09/13

REPOSITORIES: GEO

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Project description:Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

2020-08-28 | GSE156982 | GEO

Depletion of oocyte dynamin-related protein 1 shows maternal effect abnormalities in embryonic development

Project description:Eggs contain about 200,000 mitochondria that generate ATP and metabolites essential for oocyte and embryo development. In addition to this energetic role, mitochondria also integrate the cellular metabolic and transcriptional state via metabolites which regulate epigenetic modifiers. The maternal epigenome is established during oogenesis, but there is no direct evidence linking oocyte mitochondrial function to the maternal epigenome and embryo development. The DRP1 protein is required for mitochondrial fission. Here, we demonstrate a dramatic maternal effect in that DRP1-deficient oocytes fertilized by wild-type sperm exhibit a high frequency of failure in peri- and post-implantation development. This failure is associated with altered oocyte mitochondrial function, changes in the oocyte transcriptome and proteome, and a decrease in oocyte DNA methylation and H3K27me3. Transplanting the pronuclei of these fertilized oocytes to normal ooplasm fails to rescue embryonic lethality. We conclude that mitochondrial function plays a role in establishing the maternal epigenome, with serious consequences for embryo development.

2021-11-01 | GSE180579 | GEO

Crosstalk between Drp1 phosphorylations during mitochondrial remodelling and their impact on metabolic adaptation - Parallel reaction monitoring (PRM) mass spectrometry-based proteomic data

Project description:Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine intracellular mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator Drp1, at S579 or S600. This dataset is linked to a study reporting on how in differentiated mouse tissues Drp1 phosphorylation at S600 acted as an upstream event for S579 phosphorylation, leading to mitochondrial fragmentation. We performed liquid chromatography mass spectrometry (LC-MS) analyses in phospho-Drp1 immunoprecipitates from BAT of vehicle or CL316,243-treated mice, following digestion with endoproteinase Glu-C to assess whether S600 and S579 phosphorylations were both occurring in the same Drp1 proteoforms or individually in different pools of Drp1 proteins. Our results certify that upon PKA stimulation, S600 and S579 phosphorylations occurred simultaneously on the same Drp1 molecular form.

2021-08-26 | PXD027108 | Pride

Disruption of Drp1 in the liver protects mice against diet-induced obesity through induction of fibroblast growth factor 21

Project description:Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondrial-associated ER membrane. Recently, great advances have been made in the understanding of inter-organelle communication between the ER and mitochondria. To clarify the role of mitochondrial dynamics in this communication, we generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (Drp1) in the liver (Drp1LiKO). While intake of a high-fat diet (HFD) resulted in histological changes characterized by hepatic steatosis, inflammation, apoptosis, necrosis and fibrosis, reminiscent of nonalcoholic steatohepatitis, Drp1LiKO mice showed decreased fat mass and were protected from HFD-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of fibroblast growth factor 21 (Fgf21) through induction of activating transcription factor 4 and X-box binding protein 1, master regulators of the integrated stress response.

2015-06-01 | GSE64222 | GEO

Drp1 Controls Complex II assembly and Fatty Acid Oxidation by Sdhaf2 Action on Mitochondria

Project description:The Dynamin-related GTPase, Drp1 (encoded by Dnm1l) plays a central role in mitochondrial fission and is requisite for numerous cellular processes however its role in oxidative metabolism remains unclear. Herein, we show that among human tissues, skeletal muscle exhibits the strongest correlations with the DNM1L gene. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and accumulation of intramyocellular lipids along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced Complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2, normalized Complex II activity and lipid oxidation in Drp1-KD myocytes. Drp1 appears critical in maintaining mitochondrial Complex II assembly and fatty acid oxidation, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle lipid metabolism which is of clinical significance in combatting metabolic diseases.

2024-01-26 | GSE248081 | GEO

Trafficking of Ectopic ATP Synthase via Mitochondrial Fission

Project description:Ectopic ATP synthase is a functional onco-protein increases cell proliferation when transported to plasma membrane of cancer cells. Our previous study performed large scale gene silencing screening indicated ER and mitochondrial transport pathways may lead to ectopic ATP synthase expression. Silencing dynamin-related protein 1 (Drp1), mitofusin-1 (Mfn1) and Parkin affected ectopic ATP synthases expression. However, the underlying trafficking mechanism is poorly understood. Here, we analyzed our membrane and mitochondrial proteome of lung cancer A549 cells and found that both nuclear-encoded ATP synthase subunits and mitochondrial-encoded components-ATP6 translocated to cell surface, indicating that ATP synthase subunits assembled in mitochondria. Furthermore, serum starvation enhanced ATP synthase translocation to plasma membrane, Mdivi-1, a chemical inhibitor of the mitochondrial fission protein Drp1, rescued the phenomena. Additionally, image quantification of mitochondria, showing that mitochondrial fission preference cells expressed more eATP synthase. Therefore, we proposed that eATP synthase trafficking may be related to mitochondrial dynamics. Additionally, ICC and flow cytometry revealed the expression of a critical transcription factor associated with high-risk neuroblastoma, MYCN, correlated with eATP synthase expression. To better understand whether MYCN mediated mitochondrial fission and affected ATP synthase trafficking, we first analyzed MYCN ChIP-sequencing data and found Drp1, Mfns and Parkin possessed the consensus DNA-binding motif of MYCN. Further high-resolution image analysis showed higher mitochondrial fission and eATP synthase expression in MYCN-amplified neuroblastoma. Last, silencing MYCN reduced the fission level by detecting DRP1. In summary, we suggest that trafficking of ectopic ATP synthase may via mitochondrial dynamics.

2023-05-10 | PXD007036 | Pride

Fine-tuned repression of Drp1 driven mitochondrial fission primes a ‘stem/progenitor-like state’ to accelerate neoplastic transformation

Project description:Mitochondria based priming of a stem/progenitor-like state involves fine-tuned repression of the master regulator of mitochondrial fission, Drp1, and drives carcinogen induced transformation in a keratinocyte model

2021-04-10 | GSE171772 | GEO

Targeting of mitochondrial fission through natural flavonones elicits anti-myeloma activity

Project description:Background Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in cancer pathobiology, making mitochondria-targeting therapies a promising avenue for the treatment of several cancers, including multiple myeloma (MM). Flavonones are natural flavonoids endowed with mitochondrial-targeting activities. Herein, we investigated the capability of two flavonones, Hesperetin (Hes) and Naringenin (Nar), to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. Results Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcription activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hes and Nar, was capable to recapitulate the phenotypic and molecular perturbations of each flavonone, triggering anti-MM activity in vivo. Conclusion Hes and Nar inhibit proliferation, induce apoptosis and rewire the metabolism of MM cells via the targeting of the mitochondrial fission pathway.

2024-03-06 | GSE253452 | GEO

mTORC2-NDRG1-Cdc42 axis couples fasting to mitochondrial fission

Project description:Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at Ser336 sustains mitochondrial fission and respiratory sufficiency. Timelapse imaging shows that NDRG1, but not phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in both control and Drp1-deficient cells, reflecting independency from Drp1. Using proteomics, an siRNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase Cdc42 and effectors and regulators of Cdc42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants, and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

2023-04-27 | PXD041696 | Pride

Mitochondrial dynamics define muscle fiber type by modulating cellular metabolism pathways

Project description:Skeletal muscle is highly developed after birth, consisting of glycolytic fast- and oxidative slow-twitch fibers; however, the mechanisms of fiber type-specific differentiation are poorly understood. Here, we found an unexpected role for mitochondrial fission in the differentiation of fast-twitch oxidative fibers. Depletion of the mitochondrial fission factor dynamin-related protein 1 (Drp1) in mouse skeletal muscle and cultured myotubes resulted in the specific reduction of fast-twitch muscle fibers independently of respiratory function. Altered mitochondrial fission caused the activation of the Akt/mammalian target of rapamycin (mTOR) pathway via the mitochondrial accumulation of mTOR complex 2 (mTORC2), and rapamycin administration rescued the reduction of fast-twitch fibers in vivo and in vitro. Under Akt/mTOR activation, the mitochondria-related cytokine growth differentiation factor-15 was upregulated, which repressed fast-twitch fiber differentiation. Our findings reveal a novel role for mitochondrial dynamics in the activation of mTORC2 on mitochondria, resulting in the differentiation of muscle fibers.

2023-04-01 | GSE228362 | GEO

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