“One of the reasons I find mitochondria so fascinating is because they have their own genetic material that is very different to nuclear DNA. That means the rules that apply to nuclear genetic disorders don’t apply to mitochondrial diseases, which makes studying them challenging,” says Dr Alessandro Prigione. He and his team at the MDC recently developed the first stem-cell based model for mitochondrial disease. Having moved between the fields of mitochondrial and stem-cell research, Prigione recognises the value of interdisciplinary research, “It’s a lot easier to think outside the box when you belong to more than one box or have team members from outside.”
Mitochondrial diseases are inherited from the mother
Mitochondria are cellular powerhouses critical for energy production. Children with mitochondrial disease suffer symptoms affecting the nervous system, heart and muscles because these cells rely more on mitochondrial energy than other parts of the body. Depending on the severity of the disease, some of them do not live to adulthood.
We inherit mitochondrial DNA from our mother, in contrast to nuclear DNA which we inherit in equal parts from both parents. Last year the birth of a “three-parent” baby demonstrated that mitochondrial-replacement therapy is possible, but most mothers don’t know that they carry genes for mitochondrial disease. Cells have many mitochondria that are not all identical and the number carrying the mutation varies. This means a mother with very few affected mitochondria in her own body cells may produce egg cells with large numbers of them, but be unaware of this until she has a child with a mitochondrial disease.
Making cellular models with iPS cells
Prigione started work on mitochondrial diseases during his PhD at the University of California, Davis. He moved into stem cell research for postdoctoral fellowships at the San Raffaele Scientific Institute in Milan and the MPI for Molecular Genetics in Berlin. “I realised that the stem-cell field was very much focused on the nucleus, while mitochondria and energy metabolism were under studied,” Prigione observes. He analysed how mitochondria change when cells are reprogrammed to make induced pluripotent stem (iPS) cells. This paved the way to using stem cells to create models of mitochondrial disease. “In a way I’m back where I started from, but with a completely different perspective and using a new set of tools,” Prigione says.
Studying mitochondrial disease in the lab is difficult. “The highly refined techniques we use to modify genes in the nucleus just don’t work for mitochondrial DNA,” Prigione explains. This makes the diseases hard to study in animals. Current cell-based models are not effective at modelling the interplay between mitochondrial and nuclear genes that is specific to each individual patient. At the MDC, Prigione set out to create a model for mitochondrial disease using iPS cells. “A system derived from patient cells is ideal for personalised medicine to treat rare diseases,” he says.
In a recent paper Prigione and his team present neural progenitor cells as a model for mitochondrial disease. They expected the cells would just be an intermediate step in experiments where they were differentiating iPS cells into neurons. But when they discovered the cells rely on mitochondrial respiration, they realised they could be a model for drug discovery. “Be prepared to embrace unexpected results – they can reveal important biological aspects and still be used to reach your long-term goals, even if not according to your original plan,” Prigione says. “The most important thing is to collect solid data which means you need to know the model you are working on.” The lab is now using their new model to test drugs that might be able to treat mitochondrial disease, starting with FDA-approved drugs. “If you can find a potential drug that has already been approved to treat other illnesses, it means you can move to trials in patients much sooner,” Prigione explains. Collaborations within the Berlin Institute of Health will also speed up this process.
Having a foot in both camps has allowed Prigione to combine stem-cell research and mitochondrial research in new ways. His career choices so far have used his strengths, following his interests and passion. “Things often go wrong in science. Always try to have several strategies so that if plan A doesn’t work out you’re ready with plans B and C” Prigione says, “And of course you need to be patient. That is always the hardest part.”
Accompanying Press Release
Some diseases are untreatable because we lack a model system to fully understand symptoms or test possible drugs. This is the case of mitochondrial disease, a rare condition caused by defects in the “cellular powerhouse.” Scientists from the MDC have now developed a new personalized strategy to address mitochondrial disease by reprogramming the patients' cells and used it to identify a promising potential drug.
Carmen Lorenz1,2, Pierre Lesimple3,4,5, Raul Bukowiecki1, Annika Zink1,6, Gizem Inak1, Barbara Mlody1, Manvendra Singh1, Marcus Semtner1, Nancy Mah6, Karine Auré3,4,5, Megan Leong1, Oleksandr Zabiegalov1, Ekaterini-Maria Lyras6, Vanessa Pfiffer1, Beatrix Fauler7, Jenny Eichhorst9, Burkhard Wiesner9, Norbert Huebner1, Josef Priller2,6,8, Thorsten Mielke7, David Meierhofer7, Zsuzsanna Izsvák1, Jochen C. Meier1,10, Frédéric Bouillaud3,4,5, James Adjaye11, Markus Schuelke6, Erich E. Wanker1, Anne Lombès3,4,5, Alessandro Prigione1 (2017): “Human iPSC-derived neuronal progenitors are an effective drug discovery model for neurological mitochondrial DNA disorders.” Cell Stem Cell. doi:
1Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; 2Berlin Institute of Health (BIH ), Berlin, Germany 3INSERM, Institut Cochin, Paris, France; 4CNRS, Paris, France; 5Université Paris Descartes, France; 6Charité Universitätsmedizin, Berlin, Germany; 7Max Planck Institute for Molecular Genetics, Berlin, Germany; 8DZNE, Berlin, Germany; 9Leibniz Institut für Molekulare Pharmakologie (FMP), Berlin, Germany; 10Zoological Institute, Braunschweig, Germany; 11Institute for stem cell research and regenerative medicine, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Carmen Lorenz and Pierre Lesimple are first co-authors. Anne Lombès and Alessandro Prigione are senior co-authors.
Featured image: These are colonies of neural progenitor cells, which were derived from human induced pluripotent stem cells. Colors code for proteins specific for the cell type. Image: Gizem Inak, Prigione Team, MDC