Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

Liu, Xiufei; Qu, Hua; Zheng, Yi; Liao, Qian; Zhang, Linlin; Liao, Xiaoyu; Xiong, Xin; Wang, Yuren; Zhang, Rui; Wang, Hui; Tong, Qiang; Liu, Zhenqi; Dong, Hui; Yang, Gangyi; Zhu, Zhiming; Xu, Jing; Wang, Cong-Yi

doi:10.15252/emmm.201809390

Cited by 29 publications

(22 citation statements)

References 65 publications

(91 reference statements)

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“…5 inset) (41). Recently, the glycerol phosphate shuttle has been shown to regulate macrophage inflammatory responses (42) and promote skeletal muscle regeneration (43), supporting the concept that it could be involved in the observed metabolic differences between LLO118 and LLO56 T cells.…”

Section: Identification Of Metabolic Pathway Differences Between the mentioning

confidence: 81%

Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4+ T Cells

et al. 2020

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The contribution of self-peptide-MHC signaling in CD4 + T cells to metabolic programming has not been definitively established. In this study, we employed LLO118 and LLO56, two TCRtg CD4 + T cells that recognize the same Listeria epitope. We previously have shown that LLO56 T cells are highly self-reactive and respond poorly in a primary infection, whereas LLO118 cells, which are less selfreactive, respond well during primary infection. We performed metabolic profiling and found that naive LLO118 had a dramatically higher basal respiration rate, a higher maximal respiration rate, and a higher glycolytic rate relative to LLO56. The LLO118 cells also exhibited a greater uptake of 2-NBD-glucose, in vitro and in vivo. We extended the correlation of low self-reactivity (CD5 lo) with high basal metabolism using two other CD4 + TCRtg cells with known differences in self-reactivity, AND and Marilyn. We hypothesized that the decreased metabolism resulting from a strong interaction with self was mediated through TCR signaling. We then used an inducible knock-in mouse expressing the Scn5a voltage-gated sodium channel. This channel, when expressed in peripheral T cells, enhanced basal TCR-mediated signaling, resulting in decreased respiration and glycolysis, supporting our hypothesis. Genes and metabolites analysis of LLO118 and LLO56 T cells revealed significant differences in their metabolic pathways, including the glycerol phosphate shuttle. Inhibition of this pathway reverts the metabolic state of the LLO118 cells to be more LLO56 like. Overall, these studies highlight the critical relationship between peripheral TCR-self-pMHC interaction, metabolism, and the immune response to infection. ImmunoHorizons, 2020, 4: 485-497.

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Section: Identification Of Metabolic Pathway Differences Between the mentioning

confidence: 81%

Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4+ T Cells

et al. 2020

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“…Recently, mGPDH was reported to be involved in hepatic gluconeogenesis, but the role of mGPDH in hepatic lipid homeostasis is still unclear. During our study of mGPDH in the context of skeletal muscle regeneration, lower mGPDH expression was observed in the livers of ob/ob mice relative to lean mice, which indicated possible relationships for mGPDH with hepatic lipid metabolism and steatosis.…”

mentioning

confidence: 76%

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Zheng

Xiong

et al. 2019

Hepatology

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Mitochondrial glycerol 3‐phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high‐fat diet [HFD] and db/db). Liver‐specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet‐induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA‐sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)‐related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)‐induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion–induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca2+ chelator 1,2‐bis (2‐aminophenoxy) ethane N,N,N´,N´‐tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, or cyclophilin‐D (Cyp‐D) knockdown. mGPDH promoting Cyp‐D ubiquitination was also observed. Finally, liver‐specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion: mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp‐D ubiquitination, a key regulator of the mitochondrial Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.

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“…PVDF membranes were blocked with 5% dry milk for 1 h. Membranes were incubated in the primary antibody overnight at 4°C. The following antibodies were used in Western blotting: PRR [18] (1:1,000; anti-ATP6IP2/ab40790, Abcam, MA), PGC-1α [19] (1:1000, ab54481, Abcam), NRF-1 [20] (1:1000, ab34682, Abcam, MA), mtTFA [21] (1:1000, ab131607, Abcam), p-AMPK [22, 23] (1:1000, 2535S, CST), t-AMPK [23] (1:1000, 2532S, CST), SIRT-1 [24] (1:1000, 9475S, CST). The membranes were then incubated with the corresponding secondary antibody (1:2000, horseradish peroxidase-conjugated anti-rabbit) in TBST-5% nonfat milk for 1 h at room temperature, and the immunoreactive bands were visualized followed by incubation with horseradish peroxidase-labeled IgG (1:5000).…”

Section: Methodsmentioning

confidence: 99%

Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney

Akhtar

Siragy

2019

PLoS ONE

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Abnormal mitochondrial biogenesis and function has been linked to multiple diseases including diabetes. Recently, we demonstrated the role of renal (Pro)renin receptor (PRR) in the dysregulation of mitochondria. We hypothesized that PRR contributes to the reduction of mitochondrial biogenesis and function in diabetic kidney via PGC-1α/AMPK/SIRT-1 signaling pathway. In vivo and in vitro studies were conducted in C57BL/6 mouse and mouse renal mesangial cells (mRMCs). Control and streptozotocin-induced diabetic mice were injected with scramble or PRR shRNA and followed for a period of eight weeks. PRR mRNA and protein expression increased by 44% and 39% respectively (P<0.05) in kidneys of diabetic mice, and in mRMCs exposed to high glucose by 43 and 61% respectively compared to their respective controls. These results were accompanied by reduced mRNA and protein expressions of PGC-1α (67% and 75%), nuclear respiratory factors (NRF-1, 48% and 53%), mitochondrial transcriptional factor A (mtTFA, 56% and 40%), mitochondrial DNA copy number by 75% (all, P<0.05), and ATP production by 54%, respectively in diabetic kidneys and in mRMCs exposed to high glucose. Compared to non-diabetic control mice, PRR knockdown in diabetic mice and in mRMCs, not only attenuated the PRR mRNA and protein expression but also normalized mRNA and protein expressions of PGC-1α, NRF-1, mtTFA, mitochondrial DNA copy number, and ATP production. Treatment with AMPK inhibitor, Compound C, or SIRT-1 inhibitor, EX-527, alone, or combined with PRR siRNA caused marked reduction of mRNA expression of PGC-1α, NRF-1 and mtTFA, and ATP production in mRMCs exposed to high glucose. In conclusion, our study demonstrated the contribution of the PRR to the reduction of mitochondrial biogenesis and function in diabetic kidney disease via decreasing AMPK/SIRT-1/ PGC-1α signaling pathway.

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Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

Cited by 29 publications

References 65 publications

Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4+ T Cells

Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4+ T Cells

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney

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