Metabolism
- Mitochondrial hyperfusion causes neuropathy in a fly model of CMT2A
Charcot‐Marie‐Tooth neuropathy type 2A is thought to be caused by impaired mitochondrial fusion. A study in this issue now establishes a fly model to show that mainly increased mitochondrial fusion drives CMT2A.
EMBO Reports (2018) 19: e46502
- © 2018 The Authors
- Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy
- Najla El Fissi1,
- Manuel Rojo2,
- Aїcha Aouane1,
- Esra Karatas2,
- Gabriela Poliacikova1,
- Claudine David2,
- Julien Royet1 and
- Thomas Rival (thomas.rival{at}univ-amu.fr)*,1
- 1Aix Marseille University, CNRS, IBDM, Marseille, France
- 2University of Bordeaux, CNRS, Institut de Biochimie et Génétique Cellulaires (IBGC), UMR 5095, Bordeaux, France
- ↵*Corresponding author. Tel: +33 491 26 92 42; Fax: +33 491 69 89 77; E‐mail: thomas.rival{at}univ-amu.fr
In vivo expression in Drosophila motor neurons reveals that the two most prevalent forms of mitofusin alleles associated with CMT2A neuropathy (R94Q and R364W) have opposite effects on mitochondrial fusion.
Synopsis
In vivo expression in Drosophila motor neurons reveals that the two most prevalent forms of mitofusin alleles associated with CMT2A neuropathy (R94Q and R364W) have opposite effects on mitochondrial fusion.
Mutations near/within the GTP‐binding domain of mitofusin (R94Q and T105M) inhibit fusion and trigger aggregation.
Mutations within Helix‐Bundle 1 (R364W and L76P) enhance mitochondrial fusion.
Aggregation and excess fusion both impact on mitochondrial distribution and turn over and induce locomotor defects in Drosophila.
EMBO Reports (2018) 19: e45241
- Received September 26, 2017.
- Revision received May 16, 2018.
- Accepted May 23, 2018.
- © 2018 The Authors
- Mitochondrial adaptation in obesity is a ClpPicated business
Quality control systems that maintain mitochondrial oxidative phosphorylation (OXPHOS) include rescue by mitochondrial fusion, elimination of dysfunctional mitochondria by mitophagy, and degradation of damaged proteins by proteases. ClpP is an ATP‐dependent protease located in the mitochondrial matrix and mutated in Perrault syndrome, causing gonadal atrophy and hearing loss. Given that hearing loss is common in mitochondrial diseases caused by mtDNA mutations, ClpP was proposed to be part of the quality control system to maintain proper mitochondrial OXPHOS function. Two recent studies independently report that deletion of ClpP in mice protects from insulin resistance and obesity by increasing mitochondrial OXPHOS capacity and browning in gonadal white adipose tissue and mitochondrial coupling in brown adipose tissue [1], [2]. Furthermore, liver‐ and muscle‐specific deletion of ClpP has no major effects on insulin resistance. These studies reveal that ClpP might be involved in tissue‐specific mitochondrial remodeling in response to metabolic demands, rather than exclusively removing damaged proteins to maintain OXPHOS capacity.
See also: Becker et al (May 2018) and Bhaskaran et al (March 2018)
Two recent studies independently show that loss of the mitochondrial protease ClpP protects mice from insulin resistance and diet‐induced obesity.
EMBO Reports (2018) 19: e46295
- © 2018 The Authors
- Glutamine‐utilizing transaminases are a metabolic vulnerability of TAZ/YAP‐activated cancer cells
- Chih‐Sheng Yang1,†,
- Eleni Stampouloglou1,†,
- Nathan M Kingston1,†,
- Liye Zhang2,3,
- Stefano Monti2 and
- Xaralabos Varelas (xvarelas{at}bu.edu)*,1
- 1Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
- 2Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- 3Present Address: School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- ↵*Corresponding author. Tel: +1 617 358 4575; E‐mail: xvarelas{at}bu.edu
↵† These authors contributed equally to this work
Elevated levels of the transcriptional regulators TAZ/YAP, key effectors of Hippo pathway signalling, mediate breast cancer cell growth dependence on exogenous glutamine. Cancer cells with high TAZ/YAP activity are sensitive to transaminase inhibition.
Synopsis
Elevated levels of the transcriptional regulators TAZ/YAP, key effectors of Hippo pathway signalling, mediate breast cancer cell growth dependence on exogenous glutamine. Cancer cells with high TAZ/YAP activity are sensitive to transaminase inhibition.
High TAZ/YAP levels alter cellular energetics to promote breast cancer cell growth dependence on exogenous glutamine.
TAZ/YAP promote the expression of glutamic–oxaloacetic transaminase (GOT1) and phosphoserine aminotransferase (PSAT1).
Transaminase inhibition represses breast cancer cell growth in a TAZ/YAP dependent manner.
EMBO Reports (2018) 19: e43577
- Received October 26, 2016.
- Revision received March 19, 2018.
- Accepted March 23, 2018.
- © 2018 The Authors
- Mitochondria and the dynamic control of stem cell homeostasis
- Pawel Lisowski1,2,3,
- Preethi Kannan1,
- Barbara Mlody1 and
- Alessandro Prigione (alessandro.prigione{at}mdc-berlin.de)*,1
- 1Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany
- 2Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland
- 3Centre for Preclinical Research and Technology (CePT), Warsaw Medical University, Warsaw, Poland
- ↵*Corresponding author. Tel: +49 30 9406 2871; Fax: +49 30 9406 3696; E‐mail: alessandro.prigione{at}mdc-berlin.de
Dissecting the roles of mitochondria in stem cell homeostasis and differentiation is essential to understand stem cell dynamics and fate. This review discusses how mitochondria are implicated in the acquisition, maintenance and loss of stemness.
EMBO Reports (2018) 19: e45432
- Received November 3, 2017.
- Revision received December 22, 2017.
- Accepted March 21, 2018.
- © 2018 The Authors
- Ticking time bomb? High time for chronobiological research
- 1Institute and Policlinic for Occupational Medicine, Environmental Medicine and Prevention Research, University Hospital of Cologne, Cologne, Germany
- 2Nuffield Department of Clinical Neurosciences, Sleep and Circadian Neuroscience Institute, OMPI G, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
The 2017 Nobel prize for elucidating the mechanisms of chronobiology highlights the urgent need to better understand our internal clockwork and its effects on health and disease.
- © 2018 The Authors
- CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis
- Christina Becker1,
- Alexandra Kukat1,
- Karolina Szczepanowska1,
- Steffen Hermans1,
- Katharina Senft1,
- Christoph Paul Brandscheid1,
- Priyanka Maiti1 and
- Aleksandra Trifunovic (aleksandra.trifunovic{at}uk-koeln.de)*,1,2
- 1Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany
- 2Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
- ↵*Corresponding author. Tel: +49 221 478 84291; E‐mail: aleksandra.trifunovic{at}uk-koeln.de
Complete loss of mitochondrial CLPP protease protects mice from diet‐induced obesity and insulin‐resistance but impairs cold‐induced thermogenesis due to a decline in brown adipocyte function.
Synopsis
Complete loss of mitochondrial CLPP protease makes mice leaner with increased ability for glucose handling and protects them from diet‐induced obesity. In the same time, CLPP ablation also leads to a decline in brown adipocytes function leaving mice unable to cope with a cold‐induced stress due to dysfunctional thermogenesis.
Loss of CLPP protects against HFD‐induced obesity and insulin resistance.
CLPP deficiency increases FAO in white adipose tissue.
Loss of CLPP impairs cold‐induced thermogenesis.
EMBO Reports (2018) 19: e45126
- Received September 5, 2017.
- Revision received February 26, 2018.
- Accepted February 27, 2018.
- © 2018 The Authors
- From white to beige: a new hypothalamic pathway
Understanding how brown and beige adipocytes can be differentially controlled and activated by neuronal circuits is a fundamental prerequisite to fully comprehend the metabolic role that fat tissue plays in energy homeostasis. In this issue of EMBO reports, Wang et al [1] identify a new hypothalamic route that drives the exclusive recruitment of beige fat via the selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue. Since the data strongly suggest that the APPL2–AMPK signaling axis is crucial for this activation, this finding sheds a new light on the cross talk between peripheral homeostatic signals and neurons that are part of hypothalamic energy homeostasis regulatory pathways in the ventromedial hypothalamus (VHM) proposing a new defending mechanism to cold and obesity.
See also: B Wang et al (April 2018)
A study in this issue shows that the adaptor protein APPL2 induces activation of RIP‐Cre neurons in the VMH, which enhances sympathetic outflow to sWAT, sWAT beiging and cold tolerance.
EMBO Reports (2018) 19: e45928
- © 2018 The Authors
- Zc3h10 is a novel mitochondrial regulator
- Matteo Audano1,
- Silvia Pedretti1,
- Gaia Cermenati1,
- Elisabetta Brioschi1,
- Giuseppe Riccardo Diaferia2,
- Serena Ghisletti3,
- Alessandro Cuomo2,
- Tiziana Bonaldi2,
- Franco Salerno4,
- Marina Mora4,
- Liliana Grigore5,6,
- Katia Garlaschelli6,
- Andrea Baragetti1,6,
- Fabrizia Bonacina1,
- Alberico Luigi Catapano1,5,
- Giuseppe Danilo Norata1,6,7,
- Maurizio Crestani1,
- Donatella Caruso1,
- Enrique Saez8,
- Emma De Fabiani (emma.defabiani{at}unimi.it)*,1 and
- Nico Mitro (nico.mitro{at}unimi.it)*,1
- 1DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
- 2Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy
- 3Humanitas Clinical and Research Center, Rozzano‐Milan, Italy
- 4Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS C. Besta Neurological Institute, Milan, Italy
- 5IRCSS Multimedica, Milan, Italy
- 6SISA Centre, Bassini Hospital, Cinisello Balsamo, Italy
- 7School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Science, Curtin University, Perth, WA, Australia
- 8Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- ↵*
Corresponding author. Tel: +39 02 50318323; E‐mail: emma.defabiani{at}unimi.it
Corresponding author. Tel: +39 02 50318253; E‐mail: nico.mitro{at}unimi.it
Genome‐wide functional screens coupled to integrated omic approaches identify Zinc finger CCCH‐type containing 10 (Zc3h10) as a new regulator of mitochondrial biology. Zc3h10 silencing in vitro and mutation in vivo are associated with impaired mitochondrial function.
Synopsis
Genome‐wide functional screens coupled to integrated omic approaches identify Zinc finger CCCH‐type containing 10 (Zc3h10) as a new regulator of mitochondrial biology. Zc3h10 silencing in vitro and mutation in vivo are associated with impaired mitochondrial function.
Genomic screens identify the poorly characterized Zc3h10 as a novel mitochondrial regulator.
Zc3h10 silencing in vitro impairs mitochondrial oxidative capacity in myoblasts and delays myogenesis.
Cys105 mutation leads to Zc3h10 loss of function and is associated with compromised metabolic trait and mitochondrial dysfunction in human isolated PBMCs.
EMBO Reports (2018) 19: e45531
- Received November 22, 2017.
- Revision received February 2, 2018.
- Accepted February 7, 2018.
- © 2018 The Authors
- Oncoprotein CIP2A promotes the disassembly of primary cilia and inhibits glycolytic metabolism
- Ae Lee Jeong1,2,
- Hye In Ka1,
- Sora Han1,
- Sunyi Lee1,3,
- Eun‐Woo Lee4,
- Su Jung Soh1,
- Hyun Jeong Joo1,
- Buyanravjkh Sumiyasuren1,
- Ji Young Park1,
- Jong‐Seok Lim1,
- Jong Hoon Park1,
- Myung Sok Lee1 and
- Young Yang (yyang{at}sookmyung.ac.kr)*,1
- 1Division of Biological Sciences, Department of Life Systems, Research Center for Women's Disease, Sookmyung Women's University, Seoul, Korea
- 2New Drug Development Center, Osong Medical Innovation Foundation, Osong, Korea
- 3Drug Evaluation Group, R&D Center CJ HealthCare, Icheon, Korea
- 4Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- ↵*Corresponding author. Tel: +82‐2‐710‐9590; Fax: +82‐2‐2077‐7322; E‐mail: yyang{at}sookmyung.ac.kr
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is located at the cilia transition zone and inhibits cilia assembly and the glycolytic pathway. CIP2A depletion increases ciliated cells and cilia length and enhances the glycolytic pathway.
Synopsis
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is located at the cilia transition zone and inhibits cilia assembly and the glycolytic pathway. CIP2A depletion increases ciliated cells and cilia length and enhances the glycolytic pathway.
CIP2A depletion‐induced glycolytic activation is not dependent on cilia assembly.
Enhanced cilia assembly activates glycolytic metabolism regardless of CIP2A.
EMBO Reports (2018) 19: e45144
- Received September 11, 2017.
- Revision received February 5, 2018.
- Accepted February 8, 2018.
- © 2018 The Authors
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