PARP1 depletion improves mitochondrial and heart function in Chagas disease: Effects on POLG dependent mtDNA maintenance

PLoS Pathogens
Jake Jianjun WenNisha Jain Garg

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 note...Continue Reading

References

Jun 18, 2003·Cell·W Lee Kraus, John T Lis
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Jul 4, 2006·Free Radical Biology & Medicine·Jian-jun WenNisha Jain Garg
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Sep 8, 2017·Gut·Romana R GernerAlexander R Moschen

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Citations

Apr 2, 2020·International Journal of Molecular Sciences·Jake J WenRavi S Radhakrishnan
Oct 26, 2018·Frontiers in Genetics·Sarah Hurtado-BagèsMarcus Buschbeck
Nov 30, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Xianxiu WanNisha J Garg
Jun 20, 2020·Biochimica Et Biophysica Acta. General Subjects·Ashlesha KadamRasheedunnisa Begum
Jun 29, 2021·Frontiers in Cellular and Infection Microbiology·Xianxiu Wan, Nisha Jain Garg
Aug 19, 2021·Expert Review of Vaccines·Subhadip ChoudhuriNisha Jain Garg

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Methods Mentioned

BETA
PCR
electrophoresis
ChIP
Immunoprecipitation
ELISA
protein carbonyl assay
MDA
sedation
pull-down
pull

Software Mentioned

Image Quant
Prism5
Vevo 2100
Simple PCI
Oroboros DatLab
SPSS

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