Dataset Information

2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction

ABSTRACT: Mitochondria play a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. We find that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite 2-hydroxyglutarate (2-HG), which in turn promotes lipid droplet enlargement. We further demonstrate that 2-HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2-HG are novel stress responses to mitochondrial dysfunction.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brown Adipose Tissue

SUBMITTER: Prerana Wagle

LAB HEAD: Aleksandra Trifunovic

PROVIDER: PXD064288 | Pride | 2025-05-26

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20220506_Q1_ColID_432_3003_01.raw	Raw
	20220506_Q1_ColID_432_3003_02.raw	Raw
	20220506_Q1_ColID_432_3003_03.raw	Raw
	20220506_Q1_ColID_432_3003_04.raw	Raw
	20220506_Q1_ColID_432_3003_05.raw	Raw

Items per page:

1 - 5 of 49

Similar Datasets

Project description:The peptidase ClpP is conserved from bacteria to human. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder. Because of its known relevance for the mitochondrial unfolded protein response during cell stress, we characterized two ClpP knock-out mouse founder lines and documented similar phenotypes. Ubiquitously, ClpP absence led to accumulation of its interactor protein ClpX without transcript upregulation. Interestingly, most wild-type tissues with substantial ClpP amounts had no detectable ClpX. This inverse correlation suggests that ClpX levels and degradation are regulated by ClpP. The expectation of similar protein levels, in view of a reported association of heptameric ClpP rings with hexameric ClpX rings, was confirmed only in testis of wild-type animals. Germline tissue was exceptional also in its vulnerability to ClpP deletion, with both founder lines showing complete infertility for males and females. Otherwise, ubiquitous mitochondrial dysfunction was apparent from severe growth retardation and reduced spontaneous motor activity of the animals, and from a pronounced decrease in pre-/postnatal survival. Spermatogenesis was found aborted at the spermatid stage, acrosomes and axonemes were not formed. Overall, tissue-specific roles of ClpP were evident by this massive effect for germ cells, mild bioenergetic deficits in muscle and liver tissues, and excellent compensation in brain. ClpX was previously reported to chaperone unfolded proteins and also DNA condensation in mitochondria, so it is likely that this pathway is particularly susceptible in germ cells. In conclusion, our study indicates that the role of ClpP in quality control is indispensable during development for cells with rapid changes of mitochondrial numbers, and is relevant during aging for growth and survival of the organism. Factorial design comparing ClpP knock-out mice with wild type littermates in five different tissues (brain, testis, liver, skeletal and heart muscle)

Project description:ClpP is important for bacterial growth and plays an indispensable role in cellular protein quality control systems by refolding or degrading damaged proteins, but the role of ClpP on Enterococcus faecalis is still obscure. A clpP deletion mutant (△clpP) was constructed in E. faecalis strain OG1RF in order to elucidate a more comprehensive picture of the effect of ClpP on E. faecalis. Then the global RNA level of genes was detected by RNA sequencing and the global abundance of proteins was determined by mass spectrometer with Tandem Mass Tags (TMT) labeling. We found the ΔclpP mutant strain showed impaired growth at 20℃ or 45℃, at 5% NaCl or 2 mM H2O2. The surviving bacteria of the ΔclpP mutant strain was decreased after exposure to the high concentration of linezolid or minocycline (100 x MIC) for 96 h compared with that of the parent strain. The ΔclpP mutant strain also demonstrated decreased biofilm formation, but increased virulence in a Galleria mellonella model. The abundances of heat shock proteins, regulatory protein Spx (spxA), heat-inducible transcription repressor HrcA, transcriptional regulator CtsR, ATPase/chaperone ClpC and chaperonin GroEL increased in the ΔclpP mutant strain. The FsrA response regulator and its regulating protein gelatinase GelE, acetyl esterase/lipase, adapter protein MecA and fructose-1,6-bisphosphatase (fbp) also up regulated in the ΔclpP mutant strain. However, the abundances of ribosomal protein L4/L1 family protein (rplD) , ribosomal protein L7/L12 (rplL2), 50S ribosomal protein L13 (rplM), L18 (rplR), L20 (rplT), 30S ribosomal protein S14 (rpsN2) and S18 (rpsR) all reduced in the ΔclpP mutant strain. The dihydroorotase (pyrC), orotate phosphoribosyltransferase (pyrE) and orotidine-5'-phosphate decarboxylase (pyrF) also down regulated in the ΔclpP mutant strain. In conclusion, these results suggest that ClpP participates in stress tolerance, biofilm formation, antimicrobials tolerance, and virulence of E. faecalis.

Dataset Information

2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets