PARP1 depletion improves mitochondrial and heart function in Chagas disease

Effects on POLG dependent mtDNA maintenance

Jake Jianjun Wen, Yuhui Yin, Nisha Garg

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Chagasic cardiomyopathy is caused by Trypanosoma cruzi infection. Poly(ADP-ribose) polymerase 1 (PARP1) is known for its function in nuclear DNA repair. In this study, we have employed genetic deletion and chemical inhibition approaches to determine the role of PARP1 in maintaining mtDNA dependent mitochondrial function in Chagas disease. Our data show that expression of PARP1 and protein PARylation were increased by >2-fold and >16-fold, respectively, in the cytosolic, nuclear, and mitochondrial fractions of the human cardiac myocytes and the myocardium of wildtype (WT) mice chronically infected with T. cruzi. The nuclear and cytosolic PARP1/PAR did not interfere with the transcription and translation of the components of the mtDNA replisome machinery in infected cardiomyocytes and chagasic murine myocardium. However, PARP1 binding to Polymerase γ and mtDNA in mitochondria were increased, and associated with a loss in mtDNA content, mtDNA-encoded gene expression, and oxidative phosphorylation (OXPHOS) capacity, and an increase in mitochondrial ROS production in cells and heart of WT mice infected with T. cruzi. Subsequently, an increase in oxidative stress, and cardiac collagen deposition, and a decline in LV function was noted in chagasic mice. Genetic deletion of PARP1 or treatment with selective inhibitor of PARP1 (PJ34) improved the mtDNA content, mitochondrial function, and oxidant/antioxidant balance in human cardiomyocytes and chronically infected mice. Further, PARP1 inhibition was beneficial in preserving the cardiac structure and left ventricular function in chagasic mice. We conclude that PARP1 overexpression is associated with a decline in Pol γ-dependent maintenance of mtDNA content, mtDNA-encoded gene expression, and mitochondrial respiratory function, and subsequently contributes to an increase in mtROS and oxidative stress in chagasic myocardium. Inhibition of mitochondrial PARP1/PAR offers a novel therapy in preserving the mitochondrial and LV function in chronic Chagas disease.

Original languageEnglish (US)
Article numbere1007065
JournalPLoS Pathogens
Volume14
Issue number5
DOIs
StatePublished - May 1 2018

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Chagas Disease
Mitochondrial DNA
Maintenance
Trypanosoma cruzi
Cardiac Myocytes
Myocardium
Oxidative Stress
Poly (ADP-Ribose) Polymerase-1
Gene Expression
Oxidative Phosphorylation
Cardiomyopathies
Left Ventricular Function
Oxidants
DNA Repair
Mitochondria
Chronic Disease
Collagen
Antioxidants

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

PARP1 depletion improves mitochondrial and heart function in Chagas disease : Effects on POLG dependent mtDNA maintenance. / Wen, Jake Jianjun; Yin, Yuhui; Garg, Nisha.

In: PLoS Pathogens, Vol. 14, No. 5, e1007065, 01.05.2018.

Research output: Contribution to journalArticle

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abstract = "Chagasic cardiomyopathy is caused by Trypanosoma cruzi infection. Poly(ADP-ribose) polymerase 1 (PARP1) is known for its function in nuclear DNA repair. In this study, we have employed genetic deletion and chemical inhibition approaches to determine the role of PARP1 in maintaining mtDNA dependent mitochondrial function in Chagas disease. Our data show that expression of PARP1 and protein PARylation were increased by >2-fold and >16-fold, respectively, in the cytosolic, nuclear, and mitochondrial fractions of the human cardiac myocytes and the myocardium of wildtype (WT) mice chronically infected with T. cruzi. The nuclear and cytosolic PARP1/PAR did not interfere with the transcription and translation of the components of the mtDNA replisome machinery in infected cardiomyocytes and chagasic murine myocardium. However, PARP1 binding to Polymerase γ and mtDNA in mitochondria were increased, and associated with a loss in mtDNA content, mtDNA-encoded gene expression, and oxidative phosphorylation (OXPHOS) capacity, and an increase in mitochondrial ROS production in cells and heart of WT mice infected with T. cruzi. Subsequently, an increase in oxidative stress, and cardiac collagen deposition, and a decline in LV function was noted in chagasic mice. Genetic deletion of PARP1 or treatment with selective inhibitor of PARP1 (PJ34) improved the mtDNA content, mitochondrial function, and oxidant/antioxidant balance in human cardiomyocytes and chronically infected mice. Further, PARP1 inhibition was beneficial in preserving the cardiac structure and left ventricular function in chagasic mice. We conclude that PARP1 overexpression is associated with a decline in Pol γ-dependent maintenance of mtDNA content, mtDNA-encoded gene expression, and mitochondrial respiratory function, and subsequently contributes to an increase in mtROS and oxidative stress in chagasic myocardium. Inhibition of mitochondrial PARP1/PAR offers a novel therapy in preserving the mitochondrial and LV function in chronic Chagas disease.",
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