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Evanna Mills and Edward Chouchani share the experience of their successful mentor–mentee relationship and talk about the challenges of starting a new lab — both from a recent perspective and five years on.

A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Barnett et al. disentangle the differential contribution of mitochondrial complex I- and complex III-derived ROS to astrocytic function, with CIII-derived ROS being a major driver of neuroinflammatory responses.

This study shows that animal-based high-fat diets accelerate tumour growth and impair anti-tumour response to melanoma in obese mice, whereas plant-based high-fat diets do not.

Nitric oxide donors protect from myocardial ischemia-reperfusion injury, but the underlying mechanisms have been unclear. Edward T Chouchani et al. uncover the molecular target of such donors, a cysteine residue in a subunit of complex I of the mitochondrial respiratory chain, and suggest that this cysteine residue has a general role in regulating complex I activity and modulating ischemia-reperfusion injury.

Adipose tissue responds to a variety of hormonal and environmental cues with changes in size, cellular composition and metabolic activity. Here Kajimura and Chouchani review our current understanding of adipocyte metabolism in physiology and metabolic disease, and they discuss strategies to reprogram adipocyte fate and metabolism.

Discovery of a biochemical mechanism through which lactate binds and inhibits the SUMO protease SENP1, stimulating timed degradation of cell cycle proteins, and resulting in mitotic exit.

In the context of succinate uptake to promote adipose tissue browning, Reddy, Winther et al. show how the directionality of succinate transport across membranes is coupled with metabolic flux-derived changes in pH gradients.

A first-in-class covalent inhibitor of creatine phosphagen energetics was developed that induced toxicity in creatine kinase-dependent AML cell lines and regulated proinflammatory cytokine production in macrophages.

UCP1 is exclusively expressed in brown and beige adipocytes, where it drives thermogenesis through futile substrate cycling. Mills et al. identify a endocrine pathway mediated by the UCP1 catabolic circuit that antagonizes liver inflammation by lowering the concentration of succinate in the liver extracellular fluid.

Horng and colleagues show that mitochondrial glycerol-3-phosphate dehydrogenase, a component of the glycerol phosphate shuttle, modulates a shift from inflammation to immunosuppression in activated macrophages.

Increased glycogen metabolism in adipocytes leads to expression of uncoupling protein 1, thereby linking glucose metabolism to thermogenesis.

The mitochondrial ADP/ATP carrier mediates the proton leak in mitochondria from all tissues that lack UCP1, thereby linking coupled (ATP production) and uncoupled (thermogenesis) energy conversion.

Common protonophores—previously known as protein-independent proton translocators—activate mitochondrial heat production due to H⁺ leak through the ADP/ATP carrier and uncoupling protein 1.

In response to cold stress, mammals release norepinephrine from the sympathetic nervous system to elevate thermogenesis in brown adipose tissue (BAT) in order to maintain body temperature. This study reveals that the protein AIDA connects sympathetic input, reactive oxygen species, and uncoupling protein 1-mediated adaptive thermogenesis in BAT.

Creatine can be used for thermogenesis in adipocytes. Here Kazak et al. show that creatine uptake is required to sustain this thermogenic pathway. Knockdown of the creatine transporter, CrT, in adipocytes decreases thermogenesis and energy expenditure, whereas creatine supplementation increases energy expenditure in mice fed a high-fat diet.

Tissue nonspecific alkaline phosphatase (TNAP) within mitochondria hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation in thermogenic fat cells.

A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue.

A metabolomics study on the ischaemic heart identifies succinate as a metabolite that drives the production of reactive oxygen species and contributes to ischaemia-reperfusion injury; pharmacological inhibition of succinate accumulation ameliorates ischaemia-reperfusion injury in a mouse model of heart attack and a rat model of stroke.

Uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue is supported by a burst of mitochondrial reactive oxygen species upon cold exposure.

Metabolites have emerged as central regulators of biological function, but understanding mechanisms of metabolite regulation has proven challenging. In 2021 we have seen discoveries in the field of metabolite signalling motivated by a combination of scientific intuition and the elegant deployment of new technologies.

Gammage and colleagues find that mitochondrial DNA mutations induce alterations in redox metabolism, a remodeled tumor microenvironment characterized by a loss of neutrophils and consequently enhanced responses to immunotherapy in melanoma.

Succinate may have evolved as a signaling modality because its concentration reflects the redox state of the mitochondrial coenzyme Q pool, thus communicating to the rest of the cell and beyond about electron supply, oxygen tension and ATP demand.

WebTreatment of lipopolysaccharide-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-inflammatory transcription factor Nrf2 by alkylating key cysteine residues on the KEAP1 protein.

Intermediate metabolites of the Krebs cycle serve bioenergetic and biosynthetic needs but have recently also been linked to signalling. The authors of this Review summarize such non-metabolic signalling functions of succinate, fumarate, itaconate, 2-hydroxyglutarate isomers and acetyl-CoA in both immune cells and cancer cells.

Guillot-Sestier et al investigated sex-related differences in microglia in postmortem brain tissue from Alzheimer’s Disease (AD) patients as well as in the APP/PS1 AD mouse model. They demonstrated that there was differential expression of genes associated with microglial activation and metabolism between male and female AD mice as well as differences in morphology that were also apparent in the patient post-mortem tissue, which therefore contributes to our understanding of sexual dimorphism in AD.