scholarly journals Identification of Mfn2-S249 as a Phosphoregulatory Switch of Mitochondrial Fusion Dynamics

2022 ◽  
Author(s):  
Sanjay Kumar ◽  
Aaron Ramonett ◽  
Tasmia Ahmed ◽  
Euna Kwak ◽  
Paola Cruz Flores ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Energy Homeostasis ◽  
Mitochondrial Fusion ◽  
Cellular Respiration ◽  
Visceral Fat Accumulation ◽  
White Adipocytes ◽  
Fundamental Process ◽  
Normal Body Weight ◽  
Mitochondrial Remodeling ◽  
Direct Regulator

Mitochondrial remodeling is a fundamental process underlying cellular respiration and metabolism. Here we report TAK1 as a direct regulator of mitochondrial fusion. TAK1 is activated by a variety of mitogenic factors, cytokines and environmental stimuli, which we find induces rapid fragmentation through Mfn2 inactivation. TAK1 phosphorylates Mfn2 at Ser249, which inhibits the binding of GTP required for Mfn trans-dimerization and mitochondrial membrane fusion. Accordingly, expression of Mfn2-S249 phosphomimetics (Mfn2-E/D) constitutively promote fission whereas alanine mutant (Mfn2-A) yields hyperfused mitochondria and increased bioenergetics in cells. In mice, Mfn2-E knock-in yields embryonic lethality in homozygotes whereas heterozygotes are viable but exhibit increased visceral fat accumulation despite normal body weight and cognitive/motor functions compared to wildtype and Mfn2-A mice. Mature white adipocytes isolated from mutant mice reveal cell-autonomous TAK1-related effects on mitochondrial remodeling and lipid metabolism. These results identify Mfn2-S249 as a dynamic phosphoregulatory switch of mitochondrial fusion during development and energy homeostasis.

scholarly journals Mitochondrial Fusion in Yeast Requires the Transmembrane GTPase Fzo1p

1998 ◽  
Vol 143 (2) ◽  
pp. 359-373 ◽  
Author(s):  
Greg J. Hermann ◽  
John W. Thatcher ◽  
John P. Mills ◽  
Karen G. Hales ◽  
Margaret T. Fuller ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Fusion Reaction ◽  
Point Mutations ◽  
Integral Membrane Protein ◽  
Mitochondrial Fusion ◽  
Inner Mitochondrial Membrane ◽  
Fusion Event ◽  
Gtpase Domain ◽  
Developmentally Regulated ◽  
Mitochondrial Reticulum

Membrane fusion is required to establish the morphology and cellular distribution of the mitochondrial compartment. In Drosophila, mutations in the fuzzy onions (fzo) GTPase block a developmentally regulated mitochondrial fusion event during spermatogenesis. Here we report that the yeast orthologue of fuzzy onions, Fzo1p, plays a direct and conserved role in mitochondrial fusion. A conditional fzo1 mutation causes the mitochondrial reticulum to fragment and blocks mitochondrial fusion during yeast mating. Fzo1p is a mitochondrial integral membrane protein with its GTPase domain exposed to the cytoplasm. Point mutations that alter conserved residues in the GTPase domain do not affect Fzo1p localization but disrupt mitochondrial fusion. Suborganellar fractionation suggests that Fzo1p spans the outer and is tightly associated with the inner mitochondrial membrane. This topology may be required to coordinate the behavior of the two mitochondrial membranes during the fusion reaction. We propose that the fuzzy onions family of transmembrane GTPases act as molecular switches to regulate a key step in mitochondrial membrane docking and/or fusion.

scholarly journals Phenotypic variation in mitochondrial function across New Zealand snail populations

2017 ◽  
Author(s):  
Emma S. Greimann ◽  
Samuel F. Ward ◽  
James D. Woodell ◽  
Samantha Hennessey ◽  
Michael R. Kline ◽  
...  
Keyword(s):  
New Zealand ◽  
Mitochondrial Function ◽  
Energy Homeostasis ◽  
Environmental Gradients ◽  
Nuclear Genome ◽  
Cellular Respiration ◽  
Biological Organization ◽  
Data Set ◽  
Nuclear Interactions ◽  
Nuclear Variation

ABSTRACTMitochondrial function is critical for energy homeostasis and should shape how genetic variation in metabolism is transmitted through levels of biological organization to generate stability in organismal performance. Mitochondrial function is encoded by genes in two distinct and separately inherited genomes – the mitochondrial genome and the nuclear genome – and selection is expected to maintain functional mito-nuclear interactions. Nevertheless, high levels of polymorphism in genes involved in these mito-nuclear interactions and variation for mitochondrial function are nevertheless frequently observed, demanding an explanation for how and why variability in such a fundamental trait is maintained. Potamopyrgus antipodarum is a New Zealand freshwater snail with coexisting sexual and asexual individuals and, accordingly, contrasting systems of separate vs. co-inheritance of nuclear and mitochondrial genomes. As such, this snail provides a powerful means to dissect the evolutionary and functional consequences of mito-nuclear variation. The lakes inhabited by P. antipodarum span wide environmental gradients, with substantial across-lake genetic structure and mito-nuclear discordance. This situation allows us to use comparisons across reproductive modes and lakes to partition variation in cellular respiration across genetic and environmental axes. Here, we integrated cellular, physiological, and behavioral approaches to quantify variation in mitochondrial function across a diverse set of wild P. antipodarum lineages. We found extensive across-lake variation in organismal oxygen consumption, mitochondrial membrane potential, and behavioral response to heat stress, but few global effects of reproductive mode or sex. Taken together, our data set the stage for applying this important model system for sexual reproduction and polyploidy to dissecting the complex relationships between mito-nuclear variation, performance, plasticity, and fitness in natural populations.

scholarly journals Transgenic UCP1 in white adipocytes modulates mitochondrial membrane potential

FEBS Letters ◽  
1999 ◽  
Vol 444 (2-3) ◽  
pp. 206-210 ◽  
Author(s):  
Filip Baumruk ◽  
Pavel Flachs ◽  
Milada Horáková ◽  
Daniel Floryk ◽  
Jan Kopecký
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
White Adipocytes

scholarly journals Proteasome impairment induces recovery of mitochondrial membrane potential and an alternative pathway of mitochondrial fusion

2015 ◽  
pp. MCB.00920-15 ◽  
Author(s):  
Ryohei Shirozu ◽  
Hideki Yashiroda ◽  
Shigeo Murata
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Alternative Pathway ◽  
Mitochondrial Fusion ◽  
Yeast Cells ◽  
Mitochondrial Quality Control ◽  
Independent Manner ◽  
Cellular Integrity

Mitochondria are vital and highly dynamic organelles that continuously fuse and divide to maintain mitochondrial quality. Mitochondrial dysfunction impairs cellular integrity and is known to be associated with various human diseases. However, the mechanism by which the quality of mitochondria is maintained remains largely unexplored. Here we show that impaired proteasome function recovers the growth of yeast cells lacking Fzo1, a pivotal protein for mitochondrial fusion. Decreased proteasome activity increased the mitochondrial oxidoreductase protein Mia40 and the ratio of short isoform of mitochondrial intermembrane protein Mgm1 (s-Mgm1) to long isoform (l-Mgm1). The increase in Mia40 restored mitochondrial membrane potential, while the increase in the s-Mgm1/l-Mgm1 ratio promoted mitochondrial fusion in an Fzo1-independent manner. Our findings demonstrate a new pathway for mitochondrial quality control that is induced by proteasome impairment.

scholarly journals A Truncated Progesterone Receptor (PR-M) Localizes to the Mitochondrion and Controls Cellular Respiration

2013 ◽  
Vol 27 (5) ◽  
pp. 741-753 ◽  
Author(s):  
Qunsheng Dai ◽  
Anish A. Shah ◽  
Rachana V. Garde ◽  
Bryan A. Yonish ◽  
Li Zhang ◽  
...  
Keyword(s):  
Green Fluorescent Protein ◽  
Dna Binding ◽  
Progesterone Receptor ◽  
Western Blot ◽  
Mitochondrial Membrane ◽  
Fluorescent Protein ◽  
Cellular Respiration ◽  
Mitochondrial Localization ◽  
Localization Signal ◽  
Green Fluorescent

Abstract The cDNA for a novel truncated progesterone receptor (PR-M) was previously cloned from human adipose and aortic cDNA libraries. The predicted protein sequence contains 16 unique N-terminal amino acids, encoded by a sequence in the distal third intron of the progesterone receptor PR gene, followed by the same amino acid sequence encoded by exons 4 through 8 of the nuclear PR. Thus, PR-M lacks the N terminus A/B domains and the C domain for DNA binding, whereas containing the hinge and hormone-binding domains. In this report, we have localized PR-M to mitochondria using immunofluorescent localization of a PR-M-green fluorescent protein (GFP) fusion protein and in Western blot analyses of purified human heart mitochondrial protein. Removal of the putative N-terminal mitochondrial localization signal obviated association of PR-M with mitochondria, whereas addition of the mitochondrial localization signal to green fluorescent protein resulted in mitochondrial localization. Immunoelectron microscopy and Western blot analysis after mitochondrial fractionation identified PR-M in the outer mitochondrial membrane. Antibody specificity was shown by mass spectrometry identification of a PR peptide in a mitochondrial membrane protein isolation. Cell models of overexpression and gene silencing of PR-M demonstrated a progestin-induced increase in mitochondrial membrane potential and an increase in oxygen consumption consistent with an increase in cellular respiration. This is the first example of a truncated steroid receptor, lacking a DNA-binding domain that localizes to the mitochondrion and initiates direct non-nuclear progesterone action. We hypothesize that progesterone may directly affect cellular energy production to meet the increased metabolic demands of pregnancy.

scholarly journals SUN-584 Micrornas in Brown and White Adipocytes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Federica Dimitri ◽  
Mohammad T Alam ◽  
Lea Dib ◽  
Mark Christian
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Cell Communication ◽  
Target Prediction ◽  
Surface Proteins ◽  
White Adipocytes ◽  
A Disintegrin And Metalloproteinase ◽  
Extracellular Environment ◽  
Shivering Thermogenesis

Abstract Two types of adipose tissue exist: white (WAT) and brown (BAT). WAT stores energy while BAT consumes fatty acids and produces heat by non-shivering thermogenesis through Uncoupling Protein 1 (UCP1). BAT and WAT cooperate in maintaining energy homeostasis balance. Understanding their physiology is important for the development of treatments against diseases where this equilibrium is compromised, such as obesity and associated metabolic disorders. MicroRNAs (miRNAs) are potent gene regulators and an increasing body of evidence suggests their involvement in adipogenesis and adipose metabolism. MiRNAs can also be secreted into the extracellular environment and be taken up by distal cells, mediating cell-to-cell communication. However, very little is known about adipose tissue-derived circulating miRNAs. Through miRNA PCR array analysis we identified several miRNAs that are differentially secreted among undifferentiated and differentiated brown and white adipocytes, such as miR-196a, 378a-3p and miR-138-5p. Bioinformatics target prediction revealed that these miRNAs are potentially involved in important processes regulating the functioning of adipose tissue and its cross-talk with distal cells. Among the predicted targets of miR-196a, we identified ADAM10 (A Disintegrin And Metalloproteinase Domain-containing protein 10). This protein is responsible for the proteolytic release of several cell-surface proteins involved in numerous biological processes such as inflammation and its role could be of relevant importance in the physiopathology of the adipose tissues.

scholarly journals Leptin deficiency affects glucose homeostasis and results in adiposity in zebrafish

2021 ◽  
Author(s):  
Junling He ◽  
Yi Ding ◽  
Natalia Nowik ◽  
Charel Jager ◽  
Muhamed N. H. Eeza ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Adult Zebrafish ◽  
Insulin Resistant ◽  
Visceral Fat Accumulation ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Genes Encoding ◽  
Therapeutic Research

Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogues genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistant in zebrafish larvae, suggesting that the lepb plays a role in insulin homeostasis. In the current study, we characterised lepb-deficient (lepb-/-) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the deletion of lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb-/- adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb-/- zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb-/- adult zebrafish display the features of T2DM. Furthermore, we showed that lepb-/- adult zebrafish had glomerular hypertrophy and thickening of glomerular basement membrane, compared to control zebrafish, suggesting that lepb-/- adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb-/- mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and an attractive model to perform mechanistic and therapeutic research in T2DM and its complications.

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