PMID- 37905452
OWN - NLM
STAT- MEDLINE
DCOM- 20231206
LR  - 20240403
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 148
IP  - 23
DP  - 2023 Dec 5
TI  - Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation 
      and Heart Regeneration.
PG  - 1887-1906
LID - 10.1161/CIRCULATIONAHA.122.061192 [doi]
AB  - BACKGROUND: The importance of mitochondria in normal heart function are well 
      recognized and recent studies have implicated changes in mitochondrial metabolism 
      with some forms of heart disease. Previous studies demonstrated that knockdown of 
      the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) 
      inhibits mitochondrial translation and thereby causes a mitonuclear protein 
      imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the 
      role of these processes on cardiomyocyte proliferation. METHODS: We deleted a 
      single allele of MRPS5 in mice and used left anterior descending coronary artery 
      ligation surgery to induce myocardial damage in these animals. We examined 
      cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. 
      Doxycycline treatment was used to inhibit protein translation. Heart function in 
      mice was assessed by echocardiography. Quantitative real-time polymerase chain 
      reaction and RNA sequencing were used to assess changes in transcription and 
      chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin 
      effects. Protein levels were assessed by Western blotting and cell proliferation 
      or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end 
      labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. 
      The luciferase reporter assay was used to assess promoter activity. Mitochondrial 
      oxygen consumption rate, ATP levels, and reactive oxygen species were also 
      analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in 
      mice results in elevated cardiomyocyte proliferation and cardiac regeneration; 
      this observation correlates with improved cardiac function after induction of 
      myocardial infarction. We identified ATF4 (activating transcription factor 4) as 
      a key regulator of the mitochondrial stress response in cardiomyocytes from 
      Mrps5(+/-) mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) 
      leading to an increase in cytokinesis during cardiomyocyte proliferation. The 
      increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated 
      when one allele of Atf4 was deleted genetically (Mrps5(+/-)/Atf4(+/-)), resulting 
      in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or 
      as we also demonstrate, doxycycline treatment) activate a conserved regulatory 
      mechanism that increases the proliferation of human induced pluripotent stem 
      cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role 
      for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for 
      therapies to treat myocardial injury.
FAU - Gao, Feng
AU  - Gao F
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Liang, Tian
AU  - Liang T
AUID- ORCID: 0000-0002-1563-516X
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Lu, Yao Wei
AU  - Lu YW
AUID- ORCID: 0000-0001-6200-2974
AD  - Department of Cardiology (Y.W.L., W.T.P., D.-Z.W.), Boston Children's Hospital, 
      Harvard Medical School, Boston, MA.
FAU - Pu, Linbin
AU  - Pu L
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Fu, Xuyang
AU  - Fu X
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Dong, Xiaoxuan
AU  - Dong X
AUID- ORCID: 0000-0002-3712-3720
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Hong, Tingting
AU  - Hong T
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
FAU - Zhang, Feng
AU  - Zhang F
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Liu, Ning
AU  - Liu N
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Zhou, Yuxia
AU  - Zhou Y
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
FAU - Wang, Hongkun
AU  - Wang H
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
AD  - Key Laboratory of combined Multi-organ Transplantation, Ministry of Public 
      Health, the First Affiliated Hospital (H.W., P.L.,), Zhejiang University School 
      of Medicine, Hangzhou, China.
FAU - Liang, Ping
AU  - Liang P
AUID- ORCID: 0000-0001-6806-3735
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
AD  - Key Laboratory of combined Multi-organ Transplantation, Ministry of Public 
      Health, the First Affiliated Hospital (H.W., P.L.,), Zhejiang University School 
      of Medicine, Hangzhou, China.
FAU - Guo, Yuxuan
AU  - Guo Y
AUID- ORCID: 0000-0002-6009-4403
AD  - Institute of Cardiovascular Sciences, Peking University Health Science Center, 
      Beijing, China (Y.G.).
FAU - Yu, Hong
AU  - Yu H
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
FAU - Zhu, Wei
AU  - Zhu W
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
FAU - Hu, Xinyang
AU  - Hu X
AUID- ORCID: 0000-0002-6699-8470
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
FAU - Chen, Hong
AU  - Chen H
AUID- ORCID: 0000-0002-1906-6611
AD  - Vascular Biology Program (H.C.), Boston Children's Hospital, Harvard Medical 
      School, Boston, MA.
FAU - Zhou, Bin
AU  - Zhou B
AD  - State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell 
      Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China (B.Z.).
FAU - Pu, William T
AU  - Pu WT
AUID- ORCID: 0000-0002-4551-8079
AD  - Department of Cardiology (Y.W.L., W.T.P., D.-Z.W.), Boston Children's Hospital, 
      Harvard Medical School, Boston, MA.
FAU - Mably, John D
AU  - Mably JD
AUID- ORCID: 0000-0002-3626-9090
AD  - Center for Regenerative Medicine, University of South Florida Health Heart 
      Institute, Departments of Internal Medicine and Molecular Pharmacology and 
      Physiology, Morsani School of Medicine, University of South Florida, Tampa, FL 
      (J.D.M., D.-Z.W.).
FAU - Wang, Jian'an
AU  - Wang J
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
FAU - Wang, Da-Zhi
AU  - Wang DZ
AUID- ORCID: 0000-0003-1774-6549
AD  - Department of Cardiology (Y.W.L., W.T.P., D.-Z.W.), Boston Children's Hospital, 
      Harvard Medical School, Boston, MA.
AD  - Center for Regenerative Medicine, University of South Florida Health Heart 
      Institute, Departments of Internal Medicine and Molecular Pharmacology and 
      Physiology, Morsani School of Medicine, University of South Florida, Tampa, FL 
      (J.D.M., D.-Z.W.).
FAU - Chen, Jinghai
AU  - Chen J
AUID- ORCID: 0000-0002-5401-047X
AD  - Department of Cardiology, State Key Laboratory of Transvascular Implantation 
      Devices, Provincial Key Lab of Cardiovascular Research, Second Affiliated 
      Hospital (F.G., T.L., L.P., X.F., X.D., T.H., F.Z., N.L., H.Y., W.Z., X.H., J.W., 
      J.C.).
AD  - Institute of Translational Medicine, Zhejiang University School of Medicine 
      (F.G., T.L., L.P., X.F., X.D., F.Z., N.L., Y.Z., H.W., P.L., J.C.).
LA  - eng
GR  - R01 HL133216/HL/NHLBI NIH HHS/United States
GR  - R01 HL116919/HL/NHLBI NIH HHS/United States
GR  - R01 HL158097/HL/NHLBI NIH HHS/United States
GR  - R01 HL168900/HL/NHLBI NIH HHS/United States
GR  - R01 HL125925/HL/NHLBI NIH HHS/United States
GR  - R01 HL141853/HL/NHLBI NIH HHS/United States
GR  - R01 HL138757/HL/NHLBI NIH HHS/United States
GR  - R01 HL149401/HL/NHLBI NIH HHS/United States
GR  - R01 HL093242/HL/NHLBI NIH HHS/United States
GR  - R01 HL165794/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20231031
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - N12000U13O (Doxycycline)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Mitochondrial Proteins)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Myocytes, Cardiac/metabolism
MH  - Doxycycline
MH  - Cells, Cultured
MH  - *Induced Pluripotent Stem Cells/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Protein Biosynthesis
MH  - Cell Proliferation
MH  - Regeneration
MH  - Mitochondrial Proteins/genetics/metabolism
PMC - PMC10841688
MID - NIHMS1937645
OTO - NOTNLM
OT  - cell division
OT  - mitochondria
OT  - myocardial infarction
OT  - myocytes
OT  - regeneration
COIS- Disclosures None.
EDAT- 2023/10/31 06:42
MHDA- 2023/12/06 06:42
PMCR- 2024/12/05
CRDT- 2023/10/31 05:29
PHST- 2024/12/05 00:00 [pmc-release]
PHST- 2023/12/06 06:42 [medline]
PHST- 2023/10/31 06:42 [pubmed]
PHST- 2023/10/31 05:29 [entrez]
AID - 10.1161/CIRCULATIONAHA.122.061192 [doi]
PST - ppublish
SO  - Circulation. 2023 Dec 5;148(23):1887-1906. doi: 
      10.1161/CIRCULATIONAHA.122.061192. Epub 2023 Oct 31.