CECAD: Rudolf J. Wiesner

Research Focus Our Goals Key Publications

mtDNA Mutations in Physiological Organ Aging

All cells contain thousands of copies of mitochondrial DNA (mtDNA). Mutations of mtDNA accumulate to high levels in individual cells during the normal aging process and significantly contribute to aging-related diseases in the heart, muscle, skin, stem cells and brain.

Research Focus

Slow, physiologically relevant accumulation of mtDNA mutations can be successfully compensated by dopaminergic neurons in the Substantia nigra, but not the ventral tegmental area of mice (Paß et al., Brain, revised version submitted)

In order to understand how mtDNA mutations cause aging-related diseases and how cells prevent an extensive accumulation, we have developed a conditional transgenic mouse model showing an accelerated mutation load in any cell type of our choice. These cells then express a dominant-negative version of the mitochondrial replicative helicase Twinkle (K320E; Rosa26-loxP-Stop/Cre system). In the past, we found that very few cardiomyocytes with mitochondrial dysfunction embedded in normal tissue are sufficient to cause severe cardiac arrhythmia (Fig. 1). On the other hand, a similar mosaic in muscle neither leads to motor impairment nor to sarcopenia (aging-related muscle loss), while mtDNA mutations in muscle stem cells severely impair the capacity for muscle regeneration, a process which takes place also under non-pathological conditions during normal aging. Surprisingly, a subset of dopaminergic neurons, which degenerate in Parkinson`s disease, show a striking capacity to counteract the accumulation of mtDNA deletions and survive in K320E^DaN-mice (Fig. 2). Lately, we have described a new mechanism which selectively extracts mutated mtDNA molecules from the mitochondrial network.

Mutations of the small mitochondrial genome (mtDNA) accumulate during aging and cause aging-related diseases. We try to understand how these mutations affect organ function and how cellular quality control mechanisms counterbalance the accumulation of these mutations to keep cells healthy.

Our Goals

Physiologically relevant accumulation of few cardiomyocytes (1/200 cells) in the heart with high levels of mtDNA mutations and mitochondrial deficiency is sufficient to cause severe ventricular arrhythmia (Baris et al., Cell Metab 2015)

The group’s goal is to understand in detail how mitochondrial damage – in particular damage caused by mitochondrial DNA mutations – leads to organ dysfunction by failure of single affected cells in a tissue. The aim is to develop therapeutic approaches to slow down the process.
In collaboration with other research teams, the scientists have uncovered new important aspects of mitochondrial dysfunction in liver and muscle in connection with diabetes. They have shown that in this setting mitochondrial dysfunction is not the cause, but rather a parallel development. The group was able to demonstrate the mutagenic effect of dopamine metabolism on mtDNA – an important pathomechanism in the development of aging-associated Parkinson’s disease. The group was also the first to demonstrate that a very small number of heart muscle cells with mitochondrial dysfunction are sufficient to cause cardiac arrhythmia and that a subset of dopaminergic neurons is resistant to the accumulation of mtDNA mutations, probably the same which survive in patients suffering from Parkinson’s disease.
Our current projects aim to understand the molecular mechanisms which enable cells to avoid an extensive burden of mtDNA mutations. We manipulate mitochondrial dynamics, i.e. fusion and fission of the network, in the heart of mice with enhanced mutations in order to further accelerate or slow down the development of cardiac arrhythmia, respectively. We also analyse heart samples from patients with arrhythmia undergoing cardiac surgery to study if our findings in mice are also valid in humans. Finally, we are looking at the question how tissue stem cells, focusing on muscle satellite cells, control the accumulation of such mutations in order to remain functional throughout lifetime.

Key Publications

Paß, T., K.M. Ricke, P. Hofmann, R. Chowdhury, Y. Nie, P. Chinnery, H. Endepols, B. Neumaier, A. Carvalho, L. Rigoux, S.M. Steculorum, J. Prudent, T. Riemer, M. Aswendt, B. Liss, B. Brachvogel and R.J. Wiesner: Preserved striatal innervation maintains motor function despite severe loss of nigral dopamine neurons induced by mtDNA mutations. Brain (in revision)
Sen A, S. Kallabis, F. Gaedke, C. Jüngst, J. Boix, J. Nüchel, K. Maliphol, J. Hofmann, A.C. Schauss, M, Krüger, R.J. Wiesner, Pla-Martín D (2022): Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA. Nature Communications 13(1):6704.
Ricke, K.M., T. Paß, S. Kimoloi, K. Fährmann, C. Jüngst, A. Schauss, O.R. Baris, M. Aradjanski, A. Trifunovic, T.M. Eriksson Faelker, M. Bergami and R.J.Wiesner (2020): Mitochondrial dysfunction combined with high calcium load leads to impaired antioxidant defense underlying the selective loss of nigral dopaminergic neurons. J Neuroscience 40: 1975-1986
Weiland, D., B. Brachvogel, H.-T. Hornig-Do, J.F.G. Neuhaus, T. Holzer, D.J. Tobin, C.M. Niessen, R.J.Wiesner^# and O.R. Baris (2018): Imbalance of mitochondrial respiratory chain complexes in the epidermis induces severe skin inflammation. J Invest Dermatol 138: 132-140. ^#corresponding author
Baris, O.R., S. Ederer, J.F.G. Neuhaus, J.-C. v. Kleist-Retzow, C.M. Wunderlich, M. Pal, F.T. Wunderlich, V. Peeva, G. Zsurka, W.S. Kunz, T. Hickethier, A.C. Bunck, F. Stöckigt, J.W. Schrickel and R.J. Wiesner (2015):Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell Metabolism 21, 667-77.

Rudolf J. Wiesner

Deptartment of Physiology, Faculty of Medicine

Prof. Dr. Rudolf J. Wiesner

Research Areas