Translational regulation of mitochondrial biogenesis

2016 ◽  
Vol 44 (6) ◽  
pp. 1717-1724 ◽  
Author(s):  
Yi Zhang ◽  
Hong Xu
Keyword(s):  
Cell Growth ◽  
Mitochondrial Biogenesis ◽  
Energy Demand ◽  
Translational Regulation ◽  
Energy Homeostasis ◽  
Local Translation ◽  
Cellular Energy ◽  
Mechanistic Target Of Rapamycin ◽  
Expression Of Genes ◽  
Cell Growth And Proliferation

Mitochondria are generated by the expression of genes on both nuclear and mitochondrial genome. Mitochondrial biogenesis is highly plastic in response to cellular energy demand, developmental signals and environmental stimuli. Mechanistic target of rapamycin (mTOR) pathway regulates mitochondrial biogenesis to co-ordinate energy homeostasis with cell growth. The local translation of mitochondrial proteins on the outer membrane facilitates their efficient import and thereby allows prodigious mitochondrial biogenesis during rapid cell growth and proliferation. We postulate that the local translation may also allow cells to promote mitochondrial biogenesis selectively based on the fitness of individual organelle. MDI–Larp complex promotes the biogenesis of healthy mitochondria and thereby is essential for the selective transmission of healthy mitochondria. On the other hand, PTEN-induced putative kinase 1 (PINK1)–Pakin activates protein synthesis on damaged mitochondria to maintain the organelle homeostasis and activity. We also summarize some recent progress on miRNAs' regulation on mitochondrial biogenesis.

scholarly journals Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance

2017 ◽  
Vol 61 (6) ◽  
pp. 699-710 ◽  
Author(s):  
Charlotte E. Johnson ◽  
Andrew R. Tee
Keyword(s):  
Cell Growth ◽  
Cancer Cells ◽  
Energy Homeostasis ◽  
Cellular Stress ◽  
Growth Control ◽  
Potential Therapeutic Target ◽  
Wide Range ◽  
Cell Growth And Proliferation ◽  
Mtor Complex 1 ◽  
Cell Growth Control

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) at lysosomes plays a pivotal role in cell growth control where an array of large multiprotein complexes relay nutrient, energy, and growth signal inputs through mTORC1. In cancer cells, such regulation often becomes disconnected, leading to uncontrolled cell growth and an elevation in cellular stress. Consequently, cancer cells often lose homeostatic balance as they grow in unfavorable conditions, i.e. when nutrients and energy are limited yet mTORC1 is still aberrantly activated. Cancer cells lose signaling flexibility because of hyperactive mTORC1 that leads to heightened cellular stress and loss of nutrient and energy homeostasis, all of which are potential avenues for cancer therapy. Cancer cells often enhance mTORC1 to drive cell growth and proliferation, while also maintaining their survival. Autophagy regulation by mTORC1 is critically involved in nutrient and energy homeostasis, cell growth control, and survival. Studying mTORC1 and autophagy as a potential therapeutic target for cancer treatment has been the focus of a wide range of research over the past few decades. This review will explore the signaling pathways central to mTORC1 and autophagy regulation, and cancer vulnerabilities while considering anticancer therapies.

scholarly journals A Little AXER ABC: ATP, BiP, and Calcium Form a Triumvirate Orchestrating Energy Homeostasis of the Endoplasmic Reticulum

Contact ◽  
2020 ◽  
Vol 3 ◽  
pp. 251525642092679
Author(s):  
Richard Zimmermann ◽  
Sven Lang
Keyword(s):  
Endoplasmic Reticulum ◽  
Energy Demand ◽  
Energy Homeostasis ◽  
Atp Synthesis ◽  
Adenosine Diphosphate ◽  
High Energy ◽  
Molecular Probes ◽  
Cellular Energy ◽  
Amp Activated Protein Kinase ◽  
Acting In Concert

Pioneering work in the 1990s started to address an interesting question. How is the main cellular energy source, adenosine triphosphate (ATP), imported into the mammalian endoplasmic reticulum (ER)? Despite its high-energy demand, large volume, and structural as well as functional complexity, the ER harbors no intricate system for ATP synthesis or regeneration. Although the original biochemical reconstitution approaches established hallmarks of the ATP transport into the ER including nucleotide selectivity, affinity, and antiport mode, the more recent live-cell imaging methods employing sensitive, localized molecular probes identified the elusive ATP/adenosine diphosphate (ADP) exchanger. According to its selectivity and localization, the identified SLC35B1 protein was rebranded AXER. Here, we discuss the identification and regulation of AXER plus the cytosolic partners (AMP-activated protein kinase, AMPK) and subcellular structures (mitochondrial–ER contact sites, MERCs) acting in concert with it to orchestrate energy homeostasis of the mammalian ER. Furthermore, we combine the two seemingly controversial regulatory mechanisms (lowER and CaATiER) in a unifying hypothesis.

scholarly journals Human SWI/SNF-Associated PRMT5 Methylates Histone H3 Arginine 8 and Negatively Regulates Expression of ST7 and NM23 Tumor Suppressor Genes

2004 ◽  
Vol 24 (21) ◽  
pp. 9630-9645 ◽  
Author(s):  
Sharmistha Pal ◽  
Sheethal N. Vishwanath ◽  
Hediye Erdjument-Bromage ◽  
Paul Tempst ◽  
Saïd Sif
Keyword(s):  
Cell Growth ◽  
Cell Line ◽  
Transcriptional Activation ◽  
Tumor Suppressor Genes ◽  
Chromatin Remodelers ◽  
Protein Arginine Methyltransferases ◽  
Expression Of Genes ◽  
A Cell ◽  
Cell Growth And Proliferation ◽  
Nih 3T3

ABSTRACT Protein arginine methyltransferases (PRMTs) have been implicated in transcriptional activation and repression, but their role in controlling cell growth and proliferation remains obscure. We have recently shown that PRMT5 can interact with flag-tagged BRG1- and hBRM-based hSWI/SNF chromatin remodelers and that both complexes can specifically methylate histones H3 and H4. Here we report that PRMT5 can be found in association with endogenous hSWI/SNF complexes, which can methylate H3 and H4 N-terminal tails, and show that H3 arginine 8 and H4 arginine 3 are preferred sites of methylation by recombinant and hSWI/SNF-associated PRMT5. To elucidate the role played by PRMT5 in gene regulation, we have established a PRMT5 antisense cell line and determined by microarray analysis that more genes are derepressed when PRMT5 levels are reduced. Among the affected genes, we show that suppressor of tumorigenicity 7 (ST7) and nonmetastatic 23 (NM23) are direct targets of PRMT5-containing BRG1 and hBRM complexes. Furthermore, we demonstrate that expression of ST7 and NM23 is reduced in a cell line that overexpresses PRMT5 and that this decrease in expression correlates with H3R8 methylation, H3K9 deacetylation, and increased transformation of NIH 3T3 cells. These findings suggest that the BRG1- and hBRM-associated PRMT5 regulates cell growth and proliferation by controlling expression of genes involved in tumor suppression.

scholarly journals mTOR as a central regulator of lifespan and aging

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 998 ◽  
Author(s):  
David Papadopoli ◽  
Karine Boulay ◽  
Lawrence Kazak ◽  
Michael Pollak ◽  
Frédérick Mallette ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fuel Cell ◽  
Cell Growth ◽  
Life Span ◽  
Cellular Senescence ◽  
Cell Function ◽  
Nutrient Sensing ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Cell Growth And Proliferation

The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.

scholarly journals MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Jane E. Craig ◽  
Joseph N. Miller ◽  
Raju R. Rayavarapu ◽  
Zhenya Hong ◽  
Gamze B. Bulut ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Biogenesis ◽  
Energy Homeostasis ◽  
Cellular Function ◽  
Mitochondrial Content ◽  
Cellular Energy ◽  
Pharmacological Inhibition ◽  
Positive Regulator ◽  
Kinase Cascade ◽  
Mitochondrial Turnover

Abstract Mitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

scholarly journals Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Yu-Ju Liu ◽  
Yijuang Chern
Keyword(s):  
Neurodegenerative Diseases ◽  
Translational Control ◽  
Energy Homeostasis ◽  
Protein Translation ◽  
Translational Machinery ◽  
Cellular Energy ◽  
Mechanistic Target Of Rapamycin ◽  
Translational Regulators ◽  
Lateral Sclerosis

Impaired energy homeostasis and aberrant translational control have independently been implicated in the pathogenesis of neurodegenerative diseases. AMP kinase (AMPK), regulated by the ratio of cellular AMP and ATP, is a major gatekeeper for cellular energy homeostasis. Abnormal regulation of AMPK has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Most importantly, AMPK activation is known to suppress the translational machinery by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1), activating translational regulators, and phosphorylating nuclear transporter factors. In this review, we describe recent findings on the emerging role of protein translation impairment caused by energy dysregulation in neurodegenerative diseases.

scholarly journals MEKK3-MEK5-ERK5 Signaling Promotes Mitochondrial Degradation

2020 ◽  
Author(s):  
Jane E. Craig ◽  
Joseph N. Miller ◽  
Raju R. Rayavarapu ◽  
Zhenya Hong ◽  
Gamze B. Bulut ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Biogenesis ◽  
Energy Homeostasis ◽  
Cellular Function ◽  
Mitochondrial Content ◽  
Cellular Energy ◽  
Pharmacological Inhibition ◽  
Positive Regulator ◽  
Kinase Cascade ◽  
Mitochondrial Turnover

AbstractMitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

scholarly journals A Balanced Act: The Effects of GH–GHR–IGF1 Axis on Mitochondrial Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Bowen Hu ◽  
Hongmei Li ◽  
Xiquan Zhang
Keyword(s):  
Growth Hormone ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Energy Homeostasis ◽  
Somatic Growth ◽  
Metabolic Demand ◽  
Physiological Conditions ◽  
Cellular Energy ◽  
Gh Receptor ◽  
Selective Elimination

Mitochondrial function is multifaceted in response to cellular energy homeostasis and metabolism, with the generation of adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS) being one of their main functions. Selective elimination of mitochondria by mitophagy, in conjunction with mitochondrial biogenesis, regulates mitochondrial function that is required to meet metabolic demand or stress response. Growth hormone (GH) binds to the GH receptor (GHR) and induces the JAK2/STAT5 pathway to activate the synthesis of insulin-like growth factor 1 (IGF1). The GH–GHR–IGF1 axis has been recognized to play significant roles in somatic growth, including cell proliferation, differentiation, division, and survival. In this review, we describe recent discoveries providing evidence for the contribution of the GH–GHR–IGF1 axis on mitochondrial biogenesis, mitophagy (or autophagy), and mitochondrial function under multiple physiological conditions. This may further improve our understanding of the effects of the GH–GHR–IGF1 axis on mitochondrial function, which may be controlled by the delicate balance between mitochondrial biogenesis and mitophagy. Specifically, we also highlight the challenges that remain in this field.

A growing role for mTOR in promoting anabolic metabolism

2013 ◽  
Vol 41 (4) ◽  
pp. 906-912 ◽  
Author(s):  
Jessica J. Howell ◽  
Stéphane J.H. Ricoult ◽  
Issam Ben-Sahra ◽  
Brendan D. Manning
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Nucleic Acids ◽  
Tumour Growth ◽  
Building Blocks ◽  
Mechanistic Target Of Rapamycin ◽  
Metabolic Functions ◽  
Molecular Events ◽  
Cell Growth And Proliferation ◽  
Mtor Complex 1

mTOR [mammalian (or mechanistic) target of rapamycin] is a protein kinase that, as part of mTORC1 (mTOR complex 1), acts as a critical molecular link between growth signals and the processes underlying cell growth. Although there has been intense interest in the upstream mechanisms regulating mTORC1, the full repertoire of downstream molecular events through which mTORC1 signalling promotes cell growth is only recently coming to light. It is now recognized that mTORC1 promotes cell growth and proliferation in large part through the activation of key anabolic processes. Through a variety of downstream targets, mTORC1 alters cellular metabolism to drive the biosynthesis of building blocks and macromolecules fundamentally essential for cell growth, including proteins, lipids and nucleic acids. In the present review, we focus on the metabolic functions of mTORC1 as they relate to the control of cell growth and proliferation. As mTORC1 is aberrantly activated in a number of tumour syndromes and up to 80% of human cancers, we also discuss the importance of this mTORC1-driven biosynthetic programme in tumour growth and progression.

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