Nelli Mnatsakanyan was born and raised in Yerevan, Armenia, a small country in Eastern Europe. Raised by her father, a chemical engineer, and her mother, a high school teacher, Mnatsakanyan developed an early interest in science, particularly physics. Her fascination grew through conversations with her astrophysicist uncle, who held a doctorate in cosmic rays and often took her to his lab at the Astrophysical Observatory. "I recall him giving me an annual subscription to Science and Life, a science magazine that was the main source of scientific information in that internet-free era," she shares, emphasizing how these early experiences sparked her curiosity in the field.
Her interest in the biomedical sciences was further piqued after she faced a life-threatening condition as a child and spent months in the hospital. During that time, Mnatsakanyan began dreaming of becoming a doctor and saving lives. In Armenia, the educational system allows students to apply simultaneously to various schools, including medical school, immediately after graduating from high school. Although her medical school application was unsuccessful, Mnatsakanyan was admitted to the biophysics program at Yerevan State University. She initially attended with the hope of reapplying to medical school the following year. However, after just one month of studying biophysics and conducting experiments in the lab, she realized that she wanted to pursue a career as a research scientist in biophysics.
During her undergraduate years, Mnatsakanyan’s research focused on bacterial ATP synthase studies in Armen Trchounian's laboratory. “It was a very exciting time in ATP synthase research. Hiroyuki Noji and colleagues from the Tokyo Institute of Technology directly observed in 1997, for the first time, the rotation of ATP synthase at the single-molecule level, followed by the Nobel Prize being awarded to John Walker and Paul Boyer for their work on ATP synthase,” she recalls. The significance of these advancements in the field was exciting, and her ATP synthase studies deeply fascinated her. She decided to pursue her PhD research on ATP synthase.
Following her PhD, she completed postdoctoral training at Texas Tech University. Mnatsakanyan arrived in the United States in 2005 with her husband and their two-year-old daughter, feeling apprehensive about starting work, especially since she had never spoken English before. "I was a bit frightened to go to work the next day," she admits. Fortunately, Joachim Weber, her postdoctoral mentor, provided crucial support, helping her navigate both cultural and academic challenges. Under Weber’s mentorship, Mnatsakanyan studied the structure-function relationship and the coupling and rotation mechanism of ATP synthase using the bacterial enzyme.
Mnatsakanyan's journey continued with her attendance at the 2014 Biophysical Society Annual Meeting, where she learned about the role of mitochondrial ATP synthase in mitochondrial permeability transition and cell death, as presented by Paolo Bernardi and Elizabeth Jonas. Inspired by the new insights, she joined Jonas’s laboratory at Yale School of Medicine to investigate the leak channel formed by ATP synthase under pathological conditions. "I had numerous questions, suggestions, and ideas to test in mitochondrial ATP synthase, and I was truly excited to join Dr. Jonas’s laboratory," she says.
In her research, Mnatsakanyan sought to understand how ATP synthase, the primary ATP-producing enzyme in cells, could form a leak channel in certain pathological conditions, ultimately leading to cell death. To investigate this, she purified mitochondrial ATP synthase and conducted single-particle cryo-EM studies to identify the conformational changes that led to leak channel activation. Cryo-EM was an emerging field at the time, and Mnatsakanyan was fortunate to receive significant support from Fred Sigworth in these studies. "The field of mitochondrial permeability transition (mPT) was one of the most contentious areas of biophysics research at that time, and remains so today," she explains. “Different mitochondrial proteins have been suggested as pore-forming candidates since the first discovery of the mPT in the 1970s. Lately, the ATP synthase has been debated as a component of the mitochondrial permeability transition pore. I recall that a well-esteemed colleague even advised me to leave the field back in 2017, as it could have harmed my career. My research was one of the main meanings of my life, and I had fallen in love with this field. Because I believed so strongly in my project, I worked even harder.”
Currently, in her independent laboratory at the Penn State College of Medicine in Hershey, Pennsylvania, Mnatsakanyan and her team focus on structural and functional studies of the ATP synthase leak channel. Their research explores the role of ATP synthase in various diseases, including Alzheimer’s disease, ischemia-reperfusion injury, and diabetes. For Mnatsakanyan, one of the most rewarding aspects of her work is mentoring her trainees and watching them grow into independent scientists.
In addition to her research, Mnatsakanyan is heavily involved in the Biophysical Society, particularly the Bioenergetics, Mitochondria, and Metabolism Subgroup, through which she has connected with many collaborators. She also serves on BPS’s Committee for Professional Opportunities for Women (CPOW), where she has found valuable career development opportunities and made lifelong friendships.
When offering advice to young biophysicists, Mnatsakanyan says, "Believe in yourself, be persistent, and focus solely on science. Everything else, including a better position, recognition, and success, will follow. It is your next breakthrough discovery that will determine your future as a scientist."