PMID- 37930434
OWN - NLM
STAT- MEDLINE
DCOM- 20231107
LR  - 20231217
IS  - 1435-1803 (Electronic)
IS  - 0300-8428 (Print)
IS  - 0300-8428 (Linking)
VI  - 118
IP  - 1
DP  - 2023 Nov 6
TI  - Activation of the integrated stress response rewires cardiac metabolism in Barth 
      syndrome.
PG  - 47
LID - 10.1007/s00395-023-01017-x [doi]
LID - 47
AB  - Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the 
      mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the 
      phospholipid cardiolipin. BTHS is characterized by heart failure, increased 
      propensity for arrhythmias and a blunted inotropic reserve. Defects in 
      Ca(2+)-induced Krebs cycle activation contribute to these functional defects, but 
      despite oxidation of pyridine nucleotides, no oxidative stress developed in the 
      heart. Here, we investigated how retrograde signaling pathways orchestrate 
      metabolic rewiring to compensate for mitochondrial defects. In mice with an 
      inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem 
      cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids 
      was strongly decreased, while glucose uptake was increased. Unbiased 
      transcriptomic analyses revealed that the activation of the eIF2alpha/ATF4 axis of 
      the integrated stress response upregulates one-carbon metabolism, which diverts 
      glycolytic intermediates towards the biosynthesis of serine and fuels the 
      biosynthesis of glutathione. In addition, strong upregulation of the 
      glutamate/cystine antiporter xCT increases cardiac cystine import required for 
      glutathione synthesis. Increased glutamate uptake facilitates anaplerotic 
      replenishment of the Krebs cycle, sustaining energy production and antioxidative 
      pathways. These data indicate that ATF4-driven rewiring of metabolism compensates 
      for defects in mitochondrial uptake of fatty acids to sustain energy production 
      and antioxidation.
CI  - (c) 2023. The Author(s).
FAU - Kutschka, Ilona
AU  - Kutschka I
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Bertero, Edoardo
AU  - Bertero E
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
AD  - Department of Internal Medicine, University of Genova, Genoa, Italy.
AD  - Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino - Italian 
      IRCCS Cardiology Network, Genoa, Italy.
FAU - Wasmus, Christina
AU  - Wasmus C
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Xiao, Ke
AU  - Xiao K
AD  - Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical 
      School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 
      Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany.
FAU - Yang, Lifeng
AU  - Yang L
AD  - Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 
      Yueyang Rd, Shanghai, 200031, China.
FAU - Chen, Xinyu
AU  - Chen X
AD  - Department of Nuclear Medicine, University Clinic Wurzburg, Oberdurrbacher 
      Strasse 6, 97080, Wurzburg, Germany.
FAU - Oshima, Yasuhiro
AU  - Oshima Y
AD  - Department of Nuclear Medicine, University Clinic Wurzburg, Oberdurrbacher 
      Strasse 6, 97080, Wurzburg, Germany.
FAU - Fischer, Marcus
AU  - Fischer M
AD  - Division of Pediatric Cardiology and Intensive Care, University Hospital LMU 
      Munich, Marchioninistr. 15, 81377, Munich, Germany.
FAU - Erk, Manuela
AU  - Erk M
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Arslan, Berkan
AU  - Arslan B
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Alhasan, Lin
AU  - Alhasan L
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Grosser, Daria
AU  - Grosser D
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Ermer, Katharina J
AU  - Ermer KJ
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Nickel, Alexander
AU  - Nickel A
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Kohlhaas, Michael
AU  - Kohlhaas M
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
FAU - Eberl, Hanna
AU  - Eberl H
AD  - Department for Pharmacology and Toxicology, University of Wurzburg, Versbacher 
      Strasse 9, 97078, Wurzburg, Germany.
FAU - Rebs, Sabine
AU  - Rebs S
AD  - Department for Pharmacology and Toxicology, University of Wurzburg, Versbacher 
      Strasse 9, 97078, Wurzburg, Germany.
FAU - Streckfuss-Bomeke, Katrin
AU  - Streckfuss-Bomeke K
AD  - Department for Pharmacology and Toxicology, University of Wurzburg, Versbacher 
      Strasse 9, 97078, Wurzburg, Germany.
AD  - Clinic for Cardiology and Pneumology, Georg-August University Gottingen and DZHK 
      (German Center for Cardiovascular Research), Partner Site, Gottingen, Germany.
FAU - Schmitz, Werner
AU  - Schmitz W
AD  - Department of Biochemistry and Molecular Biology, University of Wurzburg, Am 
      Hubland, 97074, Wurzburg, Germany.
FAU - Rehling, Peter
AU  - Rehling P
AD  - University Gottingen, Institute of Biochemistry and Molecular Cell Biology, 
      Humboldtallee 23, 37072, Gottingen, Germany.
AD  - Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks 
      of Excitable Cells" (MBExC), University of Gottingen, Gottingen, Germany.
FAU - Thum, Thomas
AU  - Thum T
AD  - Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical 
      School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), 
      Nikolai-Fuchs-Strasse 1, 30625, Hannover, Germany.
AD  - Rebirth Center for Translational Regenerative Medicine, Hannover Medical School, 
      Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
FAU - Higuchi, Takahiro
AU  - Higuchi T
AD  - Department of Nuclear Medicine, University Clinic Wurzburg, Oberdurrbacher 
      Strasse 6, 97080, Wurzburg, Germany.
FAU - Rabinowitz, Joshua
AU  - Rabinowitz J
AD  - Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, 
      NJ, 08544, USA.
FAU - Maack, Christoph
AU  - Maack C
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany.
AD  - Medical Clinic I, University Clinic Wurzburg, Wurzburg, Germany.
FAU - Dudek, Jan
AU  - Dudek J
AD  - Department of Translational Research, Comprehensive Heart Failure Center (CHFC), 
      University Clinic Wurzburg, Am Schwarzenberg 15, Haus A15, 97078, Wurzburg, 
      Germany. Dudek_J@ukw.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231106
PL  - Germany
TA  - Basic Res Cardiol
JT  - Basic research in cardiology
JID - 0360342
RN  - 48TCX9A1VT (Cystine)
RN  - 0 (Antioxidants)
RN  - 0 (Fatty Acids)
RN  - 0 (Glutamates)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Barth Syndrome/genetics
MH  - Cystine
MH  - Antioxidants
MH  - Fatty Acids
MH  - Glutamates
MH  - Glutathione
PMC - PMC10628049
OTO - NOTNLM
OT  - Amino acid
OT  - Barth syndrome
OT  - Fatty acid oxidation
OT  - Metabolism
OT  - Mitochondria
OT  - Oxidative stress
COIS- CM received speaker and consultancy honoraria from Boehringer Ingelheim, 
      AstraZeneca and Novo Nordisk. TT is founder and shareholder of Cardior 
      Pharmaceuticals (outside of this study). TT filed and licensed patents about the 
      use of noncoding RNAs (outside of the paper).
EDAT- 2023/11/06 12:41
MHDA- 2023/11/07 06:45
PMCR- 2023/11/06
CRDT- 2023/11/06 11:07
PHST- 2023/02/14 00:00 [received]
PHST- 2023/10/14 00:00 [accepted]
PHST- 2023/09/29 00:00 [revised]
PHST- 2023/11/07 06:45 [medline]
PHST- 2023/11/06 12:41 [pubmed]
PHST- 2023/11/06 11:07 [entrez]
PHST- 2023/11/06 00:00 [pmc-release]
AID - 10.1007/s00395-023-01017-x [pii]
AID - 1017 [pii]
AID - 10.1007/s00395-023-01017-x [doi]
PST - epublish
SO  - Basic Res Cardiol. 2023 Nov 6;118(1):47. doi: 10.1007/s00395-023-01017-x.