Mitochondrial Akt Signaling Modulated Reprogramming of Somatic Cells

Chen, Yuhan; Su, Ching-Chieh; Deng, Wu; Lock, Leslie F.; Donovan, Peter; Kayala, Matthew A.; Baldi, Pierre; Lee, Hsiao-Chen

doi:10.1038/s41598-019-46359-6

Cited by 16 publications

(13 citation statements)

References 57 publications

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“…PTEN was found to sustain ROS production and mitochondria-dependent apoptosis through mitochondrial localization ( 4 , 5 ). Following phosphatidylinositol 3-kinase activation, AKT is transported to mitochondria ( 6 ), and then modulates the reprogramming of somatic cells and mitochondrial apoptosis ( 7 , 8 ). Staphylococcal nuclease domain-containing protein 1 (SND1), also known as p100 or TSN, is an evolutionarily conserved protein that plays multifaceted roles by acting as a transcriptional coactivator ( 9 ) or is involved in the processing of precursor messenger RNA ( 10 ), miRNA decay ( 11 ), and ubiquitination and degradation ( 12 ) through localization to the cytoplasm and nucleus during tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

et al. 2022

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Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multifunctional protein that functions mainly in the nucleus and cytoplasm. However, whether SND1 regulates cellular activity through mitochondrial-related functions remains unclear. Herein, we demonstrate that SND1 is localized to mitochondria to promote phosphoglycerate mutase 5 (PGAM5)-mediated mitophagy. We find that SND1 is present in mitochondria based on mass spectrometry data and verified this phenomenon in different liver cancer cell types by performing organelle subcellular isolation. Specifically, The N-terminal amino acids 1-63 of SND1 serve as a mitochondrial targeting sequence (MTS), and the translocase of outer membrane 70 (TOM 70) promotes the import of SND1 into mitochondria. By immunoprecipitation-mass spectrometry (IP-MS), we find that SND1 interacts with PGAM5 in mitochondria and is crucial for the binding of PGAM5 to dynamin-related protein 1 (DRP1). Importantly, we demonstrate that PGAM5 and SND1-MTS are required for SND1-mediated mitophagy under FCCP and glucose deprivation treatment as well as for SND1-mediated cell proliferation and tumor growth both in vitro and in vivo. Aberrant expression of SND1 and PGAM5 predicts poor outcomes in hepatocellular carcinoma (HCC) patients. Taken together, these findings establish a previously unappreciated role of SND1 and the association of mitochondrion-localized SND1 with PGAM5 in mitophagy and tumor progression.

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Section: Introductionmentioning

confidence: 99%

Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

et al. 2022

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“…Osteoinduction has been previously reported to involve both a Wnt/Akt, and Bmp/Akt signaling axis, however these reports did not investigate mitochondrial parameters (39,40). Additionally, Akt has been shown separately to be an stimulator of mitochondrial function and an upstream regulator of the formation of mitochondria-associated membranes (26,29). Our data indicate Akt signaling as absolutely essential for the acute stimulation of mitochondrial OCR during the process of Wnt-and BMP-mediated osteoinduction.…”

Section: Discussionmentioning

confidence: 54%

Activation of mitochondria is an acute Akt-dependent response during osteogenic differentiation

Eliseev

2020

Preprint

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Osteogenic differentiation, the process by which bone marrow mesenchymal stem/stromal (a.k.a. skeletal stem) cells and osteoprogenitors form osteoblasts, is a critical event for bone formation during development, fracture repair, and tissue maintenance. Extra-and intracellular signaling pathways triggering osteogenic differentiation are relatively well known; however, the ensuing change in cell energy metabolism is less clearly defined. Here we tested the effect of osteogenic media containing ascorbate and β-glycerol phosphate, or various osteogenic hormones and growth factors on energy metabolism in long bone (ST2)-and calvarial bone (MC3T3-E1)-derived osteoprogenitors. We show that osteogenic media, and differentiation factors, Wnt3a and BMP2, stimulate mitochondrial oxidative phosphorylation (OxPhos) with little effect on glycolysis. The activation of OxPhos occurs acutely, suggesting a metabolic signaling change rather than protein expression change. To this end, we found that the observed mitochondrial activation is Akt-dependent. Akt is activated by osteogenic media, Wnt3a, and BMP2, leading to increased phosphorylation of various mitochondrial Akt targets, a phenomenon known to stimulate OxPhos. In sum, our data provide comprehensive analysis of cellular bioenergetics during osteoinduction in cells of two different origins (mesenchyme vs neural crest) and identify Wnt3a and BMP2 as physiological stimulators of mitochondrial respiration via Akt activation.

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“…Primary hepatocytes from LSD1-LKO or control mice were plated in the XF24 plates (Agilent Technologies). OCR was measured on the Seahorse XF24 Analyzer (Agilent Technologies) using modified buffer conditions with 1XKHB buffer containing 111 mM NaCl, 4.7 mM KCl, 2 mM MgSO4, 1.2 mM Na 2 HPO 4 , 2.5 mM Glucose, 0.5mM carnitine (pH 7.4), and standard assay reagents (oligomycin, FCCP, rotenone) ( 86 ). Data within each XF24 well were normalized using postassay protein.…”

Section: Methodsmentioning

confidence: 99%

Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1

Cao¹,

Tang²,

Du³

et al. 2021

JCI Insight

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Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces the expression of onethird of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD + synthesis and limits NAD + availability in nucleus. Lsd1 knockout reduces NAD + -dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABP and PGC-1, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD + synthesis to control mitochondrial function and hepatokine production.

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Mitochondrial Akt Signaling Modulated Reprogramming of Somatic Cells

Cited by 16 publications

References 57 publications

Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

Activation of mitochondria is an acute Akt-dependent response during osteogenic differentiation

Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1

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