bims-mimbat 2025-01-19 papers

Nat Commun. 2025 Jan 13. 16(1): 229

Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.

Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.

DOI: https://doi.org/10.1038/s41467-024-54353-4

FASEB J. 2025 Jan 15. 39(1): e70307

Cold exposure and thermoneutrality similarly reduce supraclavicular brown adipose tissue fat fraction in fasted young lean adults.

Robin van Eenige, Carlijn A Hoekx, Aashley S D Sardjoe Mishre, Maaike E Straat, Mariëtte R Boon, Borja Martinez-Tellez, Patrick C N Rensen, Hermien E Kan.

Brown adipose tissue (BAT) is a metabolically highly active tissue that dissipates energy stored within its intracellular triglyceride droplets as heat. Others have previously utilized MRI to show that the fat fraction of human supraclavicular BAT (scBAT) decreases upon cold exposure, compared with baseline (i.e., pre-cooling). However, comparisons to a control group that was not exposed to cold are largely lacking. We recently developed a non-invasive dynamic MRI protocol that allows for quantifying scBAT fat fraction changes over time. Here, we aimed to study the effect of cold exposure versus thermoneutrality on fat fraction changes in human scBAT. Ten young (mean age: 21.5 ± 0.7 years), lean (mean BMI: 21.7 ± 0.5 kg/m2), 12 h-fasted volunteers (9 females; 1 male) underwent up to 70 consecutive MRI scans each on two separate study visits in a cross-over design. Participants were exposed to a temperature of 32°C for 10 scans (i.e., ±16 min), which was then either lowered to 18°C (i.e., cold exposure) or was maintained at 32°C (i.e., thermoneutrality). Dynamic fat fraction changes were quantified, and self-reported thermal perception scores were monitored. The fat fraction in scBAT decreased over time upon cold exposure (r = -.222, p < .001). Interestingly however, we also observed a decrease in scBAT fat fraction over time upon thermoneutrality (r = -.212, p < .001). No difference was observed between the two temperature conditions (p = .55), while self-reported thermal perception scores were consistently higher (i.e., colder) upon cold exposure. In the trapezius muscle and the humerus bone as control tissues, the fat fraction was unaffected in both temperature conditions. The fat fraction in subcutaneous white adipose tissue (sWAT) however, also decreased over time upon cold exposure (r = -.270, p < .001) and during thermoneutrality (r = -.190, p < .001), again with no difference (p = .92) between the two temperature conditions. In conclusion, our results show that in 12 h-fasted, healthy individuals cold exposure and thermoneutrality similarly reduce the fat fraction within scBAT and sWAT. While we interpret that the cold exposure was sufficient to induce thermogenesis, we suggest that an increased lipolytic activity within adipocytes, as a consequence of fasting, may be the primary cause of the decreased fat fraction in both sWAT and scBAT in our study. The current study highlights the potential influence of fasting on the fat fraction in scBAT and stresses the importance of inclusion of a thermoneutral control group in studies investigating the BAT-modulating effect of cold exposure.

Keywords: brown adipose tissue; cold exposure; fat fraction; magnetic resonance imaging

DOI: https://doi.org/10.1096/fj.202402415R

Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]

Reacting to reductive stress at the mitochondrial import gate.

Sylvie Callegari.

A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.

Keywords: TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin

DOI: https://doi.org/10.1016/j.tcb.2024.12.013

EMBO J. 2025 Jan 13.

NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism.

Chris A Brosey, Runze Shen, John A Tainer.

Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4's AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4's β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4's redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affinity and chaperone activity. Regulatory-domain sequestration by NADH-activated AIF directly stimulates chaperone binding and folding, revealing how AIF mediates CHCHD4 mitochondrial import. These results establish AIF as an integral component of the metazoan disulfide relay and point to NADH-activated dimeric AIF as an organizational import center for CHCHD4 and its substrates. Importantly, AIF regulation of CHCHD4 directly links AIF's cellular NAD(H) sensing to CHCHD4 chaperone function, suggesting a mechanism to balance tissue-specific oxidative phosphorylation (OXPHOS) capacity with NADH availability.

Keywords: Apoptosis-inducing Factor (AIF); CHCHD4/MIA40; OXPHOS; Small-angle X-ray Scattering (SAXS); X-ray Crystallography

DOI: https://doi.org/10.1038/s44318-024-00360-6

J Physiol. 2025 Jan 14.

Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.

Ludovica Tommasin, Andrea Carrer, Federica Boscolo Nata, Elena Frigo, Federico Fogolari, Giovanna Lippe, Michela Carraro, Paolo Bernardi.

The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+-dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Unexpectedly, ANT-dependent PT at pH 6.5 could also be stimulated by benzodiazepine-423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co-immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process. KEY POINTS: We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT). At pH 7.4, bongkrekate had little effect on Ca2+-dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Benzodiazepine-423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT-dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. ANT could be co-immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.

Keywords: ATP synthase; adenine nucleotide translocator; calcium; mitochondria; permeability transition

DOI: https://doi.org/10.1113/JP287147

Elife. 2025 Jan 13. pii: RP97981. [Epub ahead of print]13

Robust single-nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity.

Jisun So, Olivia Strobel, Jamie Wann, Kyungchan Kim, Avishek Paul, Dominic J Acri, Luke C Dabin, Jungsu Kim, Gang Peng, Hyun Cheol Roh.

Single-nucleus RNA sequencing (snRNA-seq), an alternative to single-cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying mouse adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the biological processes involved in adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.

Keywords: adipocytes; cell biology; genetics; genomics; mouse; obesity; snRNA-seq

DOI: https://doi.org/10.7554/eLife.97981