Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever
Abstract
Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.
Data availability
All data generated or analyzed during this study are included in the manuscript as source data files.
-
Expression data from exposure of BAT and WAT at 6 and 28 degrees CNCBI Gene Expression Omnibus, GSE51080.
-
BioGPS: an extensible and customizable portal for querying and organizing gene annotation resourcesBioGPS, GeneAtlas MOE430, gcrma.
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK097441)
- Shingo Kajimura
MEXT KAKENHI (15H05932,15K21744)
- Naoya Kataoka
MEXT KAKENHI (20H03418)
- Naoya Kataoka
MEXT KAKENHI (19K06954)
- Kazuhiro Nakamura
AMED (JP21gm5010002s0305)
- Kazuhiro Nakamura
JST Moonshot R&D (JPMJMS2023)
- Kazuhiro Nakamura
National Institute of Diabetes and Digestive and Kidney Diseases (DK126160)
- Shingo Kajimura
National Institute of Diabetes and Digestive and Kidney Diseases (DK125281)
- Shingo Kajimura
National Institute of Diabetes and Digestive and Kidney Diseases (DK127575)
- Shingo Kajimura
The Edward Mallinckrodt, Jr. Foundation
- Shingo Kajimura
National Heart and Lung Institute (5K08HL13527)
- Robert W McGarrah
National Heart and Lung Institute (F32HL137398)
- Scott B Crown
American Diabetes Association (1-16-INI-17)
- Phillip J White
MEXT KAKENHI (19K06954)
- Kazuhiro Nakamura
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All the animal experiments were performed following the guidelines by the UCSF Institutional Animal Care and Use Committee or by the Nagoya University Animal Experiment Committee. The protocols were approved by the committees by the Committee on the Ethics of Animal Experiments of UCSF (AN165833) and Nagoya University. All surgery was performed under anesthesia, and every effort was made to minimize suffering.
Copyright
© 2021, Yoneshiro et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,971
- views
-
- 471
- downloads
-
- 26
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.
-
- Cell Biology
Mounting evidence has demonstrated the genetic association of ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene polymorphisms with bronchial asthma and a diverse set of inflammatory disorders. However, its role in type I interferon (type I IFN) signaling remains poorly defined. Herein, we report that ORMDL3 is a negative modulator of the type I IFN signaling by interacting with mitochondrial antiviral signaling protein (MAVS) and subsequently promoting the proteasome-mediated degradation of retinoic acid-inducible gene I (RIG-I). Immunoprecipitation coupled with mass spectrometry (IP-MS) assays uncovered that ORMDL3 binds to ubiquitin-specific protease 10 (USP10), which forms a complex with and stabilizes RIG-I through decreasing its K48-linked ubiquitination. ORMDL3 thus disrupts the interaction between USP10 and RIG-I, thereby promoting RIG-I degradation. Additionally, subcutaneous syngeneic tumor models in C57BL/6 mice revealed that inhibition of ORMDL3 enhances anti-tumor efficacy by augmenting the proportion of cytotoxic CD8 positive T cells and IFN production in the tumor microenvironment (TME). Collectively, our findings reveal the pivotal roles of ORMDL3 in maintaining antiviral innate immune responses and anti-tumor immunity.