Oby Ukadike-oyer: From the campus of Harvard medical school, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Oby, your host. ThinkResearch is brought to you by Harvard Catalyst, Harvard University's clinical and translational science center, and by NCATS, the National Center for Advancing Translational Sciences.

Join us as we talk to Dr. Marjana Ndoci about the powerhouse of the cell, mitochondria, and how they offer new insights to how cells maintain their metabolic balance and potentially lead to novel therapeutic strategies. Marjana is originally from Albania and Greece and completed her bachelor's and master's degrees in Greece. In 2023, Marjana was accepted into the Max Planck Graduate School in Germany. She established a collaboration between the labs of Professor Andreas Ladurner and Professor Nora Kory at Harvard and joined the Kory Lab as a PhD student. Her research focuses on deciphering the tethering factors of mitochondrial contact sites and understanding their role in metabolic compartmentalization.

Hi, Marjana. Welcome to the show.

Marjana Ndoci: Hi, Oby. Thanks a lot for inviting me, and I'm very happy to be here with you.

Oby Ukadike-oyer: We're happy to talk to you about your life and what's happening in research and where you're going from here. Can you introduce yourself, where you are from, where you grew up, and we can kind of go from there?

Marjana Ndoci: Yes, of course. My name is Marjana Ndoci. I was born in Albania. My parents, me, and my younger sister, we emigrated to Greece, where I've lived most of my life. I studied. I went to university to study biology.

Then the last year of my degree, I had to do my master's thesis, and for that I went to Germany at the Max Planck Institute for Biology of Aging, where I stayed one year and performed my master's thesis. I absolutely loved the institute and the city. That's why the next year I started working as a technical assistant where I had the time to do research and science, but I was not overworked, so I had time to also search for PhD positions, and this is the time that I started looking for universities or institutes to start my PhD studies.

Of course, I started looking for positions in the US where I ended up. So currently I'm a shared PhD student at the School of Public Health and at the LMU in Munich.

Oby Ukadike-oyer: Oh, nice. What was your dissertation on or your master's dissertation, and how did that lead you to what you are doing in your PhD now?

Marjana Ndoci: My master's thesis was on this transcription factor, this protein that was shown to regulate longevity. So in the lab that I was working at the Max Planck Institute, we used a model system called C. elegans. It's a tiny worm where we can basically do many studies. Basically by deleting or adding different genes, you can regulate the lifespan. And since they don't live very long, you can do many fascinating experiments on them.

So I was working with transcription factor that was shown when you delete it, when this protein is not expressed, the lifespan of this worm was decreased. What I was trying to identify was protein interactions because when you know what are the protein interactions, you can maybe reveal novel functions or processes that this protein might be involved.

Oby Ukadike-oyer: What led you to do that? Is it fascinating to you? Is there anything in particular that pushed you towards that kind of work or interest in that work?

Marjana Ndoci: I was very interested in aging research and the science that they do there. It's a fascinating thing. And I applied to that lab because they were using different model systems, so I knew even if I would be working with one model system, I would definitely get experience by talking and by attending other presentations on other model systems.

Oby Ukadike-oyer: So talk to us about your research. What are you doing? What are you looking for? How did you start your research? You started to talk a little bit about that. And then what are you actively working on right now?

Marjana Ndoci: Currently, I'm working on molecular metabolism and, more specifically, on mitochondrial contact sites. So I would like to start by telling you my journey, my love for mitochondria. I think it started when I was in university, and we had these biochemistry classes. And my professor, she works with mitochondria and stress, and she was very passionate about mitochondria. And her passion, I think, was dispersed to us and specifically to me. And I think this was the point where I realized that I would love to do something with mitochondria.

Right now, as I mentioned before, I'm working with mitochondria contact sites. And for people that are not very familiar, mitochondria are tiny organelles within our cells that, I think in the textbook, come across as the powerhouse of the cell, that they produce energy. I'm sure everyone has heard about this.

Organelle biology research has long time been trying to understand what every organelle does. So they would select, let's say, mitochondria or the endoplasmic reticulum or any other type of organelle, and they would try to dissect their function, their physiology, their signaling processes that they might participate.

But now research interest has shifted towards understanding, how do these organelles communicate together? It has been shown that they can actually touch each other and connect. So what I'm trying to see and identify is the glue that connects these organelles together.

This is important because there are so many diseases that have been shown that these contact sites are dysregulated. So understanding how they are normally formed, what proteins participate, what factors participate to mediate these contact sites I think would be crucial to potentially intervene and cure these diseases.

Oby Ukadike-oyer: That's really interesting. So you're less-- I mean, not that you're not concerned with the mitochondria, but you are really looking at the in between, the fusion that's happening. How do you hope your research will be used? I kind of heard you talking about it and what you were saying about whether it's diseases, disease states, or conditions that are impacted by this-- we'll call it the glue, you said, between. And so let's say you learn and you get some information about what's there. What's next after that?

Marjana Ndoci: Great question. So far, there have been plenty of studies that are trying to elucidate this repertoire of the molecules, of the proteins that are acting as a glue between these contact sites. So I think the goal in the field would be to identify all the proteins that are participating in the formation of the contact sites to be able to target them.

The number of people that suffer from mitochondrial disorders and diseases that are associated with the dysregulation of these contact sites, it's huge. It's very big. So I think that's why it's very important elucidating this part. The aim of this would be to develop tools or mechanisms to recover these contact sites.

Oby Ukadike-oyer: What kind of diseases are impacted by the lack of this contact site is what you're saying, the lack of this connection?

Marjana Ndoci: Ooh, so many. So I would start-- the ones that come in my mind is nonalcoholic fatty liver disease. We have infectious diseases, cancer.

Oby Ukadike-oyer: And so this would have an incredible impact if you were to find something and then be able to make the connections. I know you said that many other people have been studying this and kind of looking and exploring. What have people found?

Marjana Ndoci: These contact sites have been observed, I think, since 1950s, but it's only recently that people started digging in and trying to find, what are the molecular mechanisms that are mediating this interaction, these associations?

So many labs around the world have identified specific proteins, the glue that I mentioned in the beginning that promotes these contact sites. And they would do experiments where they would delete this protein. They would see that, let's say, the mitochondria is not interacting anymore with a certain organelle.

So far, my lab is not directly investigating contact sites. They are working more on mitochondrial transporters. Since I'm a shared PhD student between Harvard and LMU, my PI was very interested in this.

Oby Ukadike-oyer: Amazing. I've heard how this can obviously impact health. It'll really change a lot of people's lives if things are able to be found that then make that connection that then change the outcomes of a disease. Are there any other things that you hope people understand from your research or take away from what you're sharing with us about what you're working on today?

Marjana Ndoci: I think what I was also personally fascinated by-- because I have not been studying contact sites my whole life. It was very interesting for me because during our studies, as I mentioned before, we study organelles independently, and it was very beautiful to me that even within the cell, this tiny cell, organelles are cooperating together to bring balance for the cell and, generally, for the organism. So cooperation and contact.

Oby Ukadike-oyer: I may step back, and I know we talked earlier, and we've been talking about mitochondria. And I feel like mitochondria you learn about pretty early on. Maybe I'd even say elementary or middle school, you're kind of introduced to it. Is there any more you would like to say or help us understand that maybe one step further from what we know about mitochondria that talks about or speaks to your research or even helps give more insight into what you've shared with us today?

Marjana Ndoci: Definitely. I think what we learn in school is that they produce energy, but mitochondria is far more than this energy factor as it has been shown in many studies to signal the cell. For example, if the cell needs to die, mitochondria is one of the first organelles that can signal the cell that now you need to die because of various stress responses. So mitochondria participate in various signaling processes, as I mentioned, in contact sites in transmitting or sensing various stresses. So the whole cell can understand and can realize, let's say, that the cell is in danger. So apart from producing energy, mitochondria are more than that.

Oby Ukadike-oyer: Excellent. What is next for your research? What are you going to do from here?

Marjana Ndoci: To be honest, I have just recently started my PhD, so I have definitely a lot more to come. It has been six months already where I'm trying to establish my protocols and my experiments, but I think it would be very, very interesting to see and identify, as I mentioned, this glue mediating these contact sites. And if I am to prove that, I think it would be interesting to use that molecule as a tool to pharmacologically regulate it and, therefore, regulate contact sites in various diseases.

Oby Ukadike-oyer: Brilliant. So I know you said you are shared between the School of Public Health and LMU. Is that--

Marjana Ndoci: LMU in Munich, yes.

Oby Ukadike-oyer: How long will you be at Harvard? How long? When do you go back to Germany? How does that work?

Marjana Ndoci: That's a very good question. So the way that I came here is a bit strange. Every time I try to explain that to people, everyone is just perplexed, and I think it would be good for other people to know if they want to do something similar.

So I think one of the main differences between Europe and the US-- so if you wanted to pursue a PhD in Europe and you have a lab, I could directly apply to your lab. However, in the US, you can do a PhD only through a graduate program.

So in Germany, I am enrolled at the IMPRS graduate school from the Max Planck Institute in Munich, which is associated with the LMU university. And I established this collaboration between the lab here at Harvard and the lab at the LMU to pursue this project.

So, basically, the idea is that I will be doing most of the research here at Harvard, and at some point during the summer, I have to go back to Germany for a few months to perform some experiments there and ultimately come back and continue my science and experiments here.

Oby Ukadike-oyer: So will you be back and forth each year? It's just one time you go back, then you come.

Marjana Ndoci: Yes. It's one time that I have to go this summer for six months, and then I will come and continue for the rest of my graduate studies here.

Oby Ukadike-oyer: Well, thank you so much for sharing about your research and about how you got to what you're doing now, and you're so early on in your PhD and kind of in your work. We look forward to catching up with you later and seeing where it is, what you've done, what you've discovered. Really look forward to hearing about that.

Marjana Ndoci: Thank you so much, Oby. It was very nice meeting you and talking to you.

Oby Ukadike-oyer: Thank you for listening. We are always looking to connect and collaborate with the research community and would like to hear from you. Please feel free to email us at onlineeducation.catalyst.harvard.edu to inquire about being a guest on the podcast.