First person – Soumyajit Mukherjee and Shreya Das Free

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Soumyajit Mukherjee and Shreya Das are co-first authors on ‘ Pyruvate plus uridine augments mitochondrial respiration and prevents cardiac hypertrophy in zebrafish and H9c2 cells’, published in JCS. Soumyajit conducted the research described in this article while a PhD student in Dr Alok Ghosh's lab at the Department of Biochemistry, University of Calcutta, Kolkata, India, where he investigated the role of mitochondrial energy metabolism in cardiac hypertrophy. He is now a Postdoctoral Scholar in the lab of Dr Purusharth I. Rajyaguru at the Department of Biochemistry, Indian Institute of Science, Bangalore, India. Shreya is a PhD student in the lab of Dr Arunima Sengupta at the Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India, investigating the molecular regulation of mitochondrial respiration during cardiomyopathy to identify potential therapeutic targets and early biomarkers.

Soumyajit Mukherjee

How would you explain the main findings of your paper in lay terms?

S.M.: Cardiovascular diseases are the leading causes of death worldwide, and the underlying mechanisms are heterogeneous. One of the most common types of cardiovascular disease is cardiac hypertrophy. The exact molecular basis for cardiac hypertrophy has been unclear to date. Here, we demonstrated using both in vitro and in vivo models that an over-the-counter drug, phenylephrine (PE), causes cell hypertrophy in rat neonatal H9c2 cardiomyocytes and induces cardiac hypertrophy in zebrafish embryos by inhibiting mitochondrial oxygen consumption rate and generating oxidative stress. Interestingly, PE treatment reduces survivability in H9c2 cells cultured in mitochondrial respiratory-proficient galactose medium. Surprisingly, we discovered that boosting mitochondrial respiration and reactive oxygen species (ROS) scavenging by supplementation with pyruvate plus uridine dramatically ameliorates PE-induced heart hypertrophy and bradycardia (low heart rate) symptoms in zebrafish embryos, and significantly prevents enlargement of H9c2 cells.

S.D.: Cardiac hypertrophy has been shown to be associated with dysregulated mitochondria and aberrant respiratory chain complex activity, which ultimately results in the generation of oxidative stress. Therefore, reversing the mitochondrial respiratory chain defects with compounds like pyruvate and uridine can serve as an effective therapeutic approach for combating cardiac hypertrophy. Pyruvate and uridine have anti-oxidant and anti-inflammatory properties and have been shown to impart cardioprotective function by preventing cardiac injury. In this study, we showed that PE treatment resulted in cardiac hypertrophy with a concomitant decrease in mitochondrial oxygen consumption rate and respiratory chain defects. The PE-treated hypertrophic cells showed a marked decrease in NDUFB8 (complex 1) and UQCRC2 (complex III) proteins, resulting in a decrease in mitochondrial membrane potential and increased ROS generation. Interestingly, supplementation with pyruvate and uridine restored oxidative phosphorylation impairments by reducing ROS generation. We also corroborated this in the zebrafish model, where pyruvate and uridine treatment following PE-induced hypertrophy resulted in a reduction in pericardial edema with a decrease in atrial and ventricular area. Therefore, our study confirmed the protective role of pyruvate plus uridine in rescuing cardiomyocytes from the deleterious effects of hypertrophy by improving mitochondrial respiratory flux and reducing oxidative stress.

Were there any specific challenges associated with this project? If so, how did you overcome them?

S.M. and S.D.: One specific challenge that we faced during this work was the proper visualization of mitochondrial distribution and networks. It took a lot of troubleshooting and effort to get a clearer picture of the mitochondrial network.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

S.M.: When we observed that pyruvate plus uridine significantly prevented the enlargement of cardiomyocytes after PE treatment and also triggered upregulated mitochondrial metabolism, this suggested a clear mechanism that boosting mitochondrial respiratory flux might prevent cardiomyocyte hypertrophy.

S.D.: There have been a few eureka moments while performing this work. However, the two moments that have stuck with me are observing the visualization of the mitochondrial network by MitoTracker Deep Red staining and the significant rescue of cardiac output upon pyruvate plus uridine treatment during cardiac hypertrophy.

Why did you choose Journal of Cell Science for your paper?

S.M.: We selected Journal of Cell Science because it is one of the most reputable journals in the field of cell biology and is well known for publishing high-quality and impactful articles. Our research fits in nicely with the focus area of JCS, which makes it the perfect venue for disseminating our findings to the scientific community. Additionally, by giving first authors the chance to present their work, JCS encourages recognition of scientists and advancement of their careers.

S.D.: Journal of Cell Science is a multidisciplinary journal with high ethical standards. Its rigorous peer review process ensures a high quality of experiments and data. The high citation score of JCS also speaks volumes about the quality of work that is published in the journal. We have referred to multiple articles published in JCS while building up this work. The theme of our work also perfectly aligns with the scope of the journal, hence we decided to publish in JCS.

Shreya Das

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

S.M.: My principal investigator, Dr Alok Ghosh, had faith in me during this study. Without his guidance and support, it would not have been feasible. His perseverance and hard work have been tremendously inspiring, always encouraging me to do my best. I also want to thank all of the lab participants and other colleagues who taught me many techniques that were essential to this study.

S.D.: My supervisor, Dr Arunima Sengupta, has been extremely supportive and motivating from the commencement of my doctoral studies to date. She believed in me and gave me a chance to work with her. Her constant grit, perseverance and humility in this scientific community have helped me in shaping myself to become a better researcher. Her dedication towards science has been a motivational support not only for me but for my other lab mates as well.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

S.M.: People conducting research in labs and making discoveries captivated me during my undergraduate years. My imagination was captured by the prospect of venturing into the unknown and advancing scientific knowledge. I was greatly impressed by seeing scientists solve difficult challenges creatively to reveal the secrets of nature. My desire to work in scientific research has been profoundly influenced by this.

S.D.: My parents have always motivated me to pursue a career in science. Apart from them, science itself has been very motivating to me. The inquisitive mind in me has always been fascinated by the prospect of unraveling new findings every day if I take up science as my career. The most interesting moments on my path so far have been the cumulative effect of tons of experimental failures, interesting observations, newer methodologies, rejections and acceptances.

Who are your role models in science? Why?

S.M.: I am lucky that I have met great mentors during my career, particularly since I began working on mitochondrial bioenergetics. Role models from different backgrounds have taught me the value of persistence in science and the need for work–life balance to nurture curiosity.

S.D.: Among the different role models at different stages in my career, two people whose contributions towards the scientific community have led me to believe in the foundation of science are Marie Curie and Dr A. P. J. Abdul Kalam. Their contributions to science, their groundbreaking discoveries and their love for science until the last day of their lives have been unparalleled, and this has immensely inspired me and hopefully will inspire many more generations in the future.

What's next for you?

S.M.: I will continue my research journey, expanding my knowledge in molecular cell biology. Next, I want to establish my laboratory.

S.D.: Currently, I am on the verge of completing my PhD and hoping to enroll for my postdoctoral studies very soon.

Tell us something interesting about yourself that wouldn't be on your CV

S.M.: My favourite hobby is playing guitar and singing, which keeps me active and energized. Trying out delicious new food is one of my favourite activities.

S.D.: When I am not thinking about science, I enjoy acrylic painting. I am also an avid world history reader and a food explorer.