PARIS–DJ-1 Interaction Regulates Mitochondrial Functions in Cardiomyocytes, Which Is Critically Important in Cardiac Hypertrophy

ABSTRACT

Mitochondrial dysfunction is one of the major pathological attributes of cardiac hypertrophy and is associated with reduced expression of PGC1α in cardiomyocytes. However, the transcriptional regulation of PGC1α remains elusive. Here, we show that parkin interacting substrate (PARIS), a KRAB zinc finger protein, prevented PGC1α transcription despite the induction of cardiomyocytes with hypertrophic stimuli. Moreover, PARIS expression and its nuclear localization are enhanced in hypertrophy both in vitro and in vivo. Knocking down PARIS resulted in mitochondrial biogenesis and improved respiration and other biochemical features that were compromised during hypertrophy. Furthermore, a PARIS-dependent proteome showed exclusive binding of a deSUMOylating protein called DJ-1 to PARIS in control cells, while this interaction is completely abrogated in hypertrophied cells. We further demonstrate that proteasomal degradation of DJ-1 under oxidative stress led to augmented PARIS SUMOylation and consequent repression of PGC1α promoter activity. SUMOylation-resistant mutants of PARIS failed to repress PGC1α, suggesting a critical role for PARIS SUMOylation in hypertrophy. The present study, therefore, proposes a novel regulatory pathway where DJ-1 acts as an oxidative stress sensor and contributes to the feedback loop governing PARIS-mediated mitochondrial function.

KEYWORDS:

• cardiac hypertrophy
• mitochondrial dysfunction
• oxidative stress
• SUMOylation
• mitochondria
• transcriptional repression

ACKNOWLEDGMENTS

We thank Ted M. Dawson (Johns Hopkins Medical Institutions, Baltimore, MD, USA) for the kind gift of PARIS Cfugw construct. We gratefully acknowledge the CSIR-IICB Central Instrument facility for allowing to use of confocal microscopes (STED, Leica, Germany; Zeiss, Germany and Olympus, Japan). We thank Sounak Bhattacharya and Banasri Das for assistance in confocal microscopy. Technical assistance provided by Santu Paul in high-resolution mass spectrometry (Orbitrap, LTQ, Thermo Fischer, USA) is gratefully acknowledged. We also thank Swapan Mandal for laboratory assistance.

This study was supported by grants (BSC 0206 and MLP 115) from the Council of Scientific and Industrial Research (CSIR), New Delhi, India. DM is a recipient of a fellowship from CSIR [31/002(1012)/2015-EMR-I].

We declare that we have no conflicts of interest with the contents of this article.

Arun Bandyopadhyay and Dibyanti Mukherjee designed the study and contributed reagents. Dibyanti Mukherjee and Vivek Chander performed experiments. Dibyanti Mukherjee, Vivek Chander, and Arun Bandyopadhyay analyzed the data. Arun Bandyopadhyay and Dibyanti Mukherjee wrote the manuscript. Arun Bandyopadhyay, Vivek Chander, Dibyanti Mukherjee edited the manuscript.