BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Remodelling of the translatome controls diet and its impact on tumorigenesis.

Fasting is associated with a range of health benefits1-6. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting7,8. We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5' untranslated regions (5' UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK-MNK-eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source9,10 that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.

Mitochondrial heterogeneity and adaptations to cellular needs.

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.

Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo. We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival.

SLC25A48 controls mitochondrial choline import and metabolism.

Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.