PHYSIOPATHOLOGICAL INFLUENCE OF MITOCHONDRIAL GENOME INSTABILITY DURING AGING

Olivier Baris, normal class researcher

olivier.baris @ univ-angers.fr (olivier.baris @ univ-angers.fr)

Keywords: Genome instability; Mitochondrial DNA; Aging; Mitochondrial Dynamics; Metabolism

State of the art and objectives

Aging is a multifactorial process progressively leading to organ dysfunction, and increased risk to develop many diseases, such as neurodegenerative disorders and cardiovascular diseases. Mitochondrial dysfunction, driven by the progressive accumulation of mutations in the mitochondrial DNA (mtDNA), has been identified as one of these factors. However, the molecular mechanisms by which mtDNA instability leads to cell and, ultimately, organ dysfunction during aging remain unclear. To approach this, we will use a mouse model with accelerated accumulation of mtDNA deletions in a tissue-specific way (K320E-Twinkle mouse) and investigate how cells displaying mitochondrial dysfunction affect the whole organ. Moreover, we will explore the mechanisms involved in the maintenance and quality control of mtDNA, and determine their fate during aging.

Main results from the last 5 years

• Identification of catecholaminergic metabolism as a driving force in the generation of mtDNA deletions (Neuhaus, Baris et al., 2014, Brain).
• Demonstration that age-related mitochondrial tissue mosaics (i.e. few cells with mitochondrial dysfunction scattered among many normal cells) in the heart are leading to ventricular arrhythmias (Baris et al., 2015, Cell Metabolism).
• Demonstration that imbalanced stoichiometry of mitochondrial respiratory chain complexes, caused by altered mtDNA maintenance, leads to inflammation in the epidermis (Weiland et al., 2018, Journal of Investigative Dermatology).

People involved

• Caroline Silveira Martinez (Post-doc)
• Morgane Le Mao (Engineer)

Main publications and patents from the 5 last years

• Weiland, D., Brachvogel, B., Hornig-Do, H.T., Neuhaus, J.F.G., Holzer, T., Tobin, D.J., Niessen, C.M., Wiesner, R.J., and Baris, O.R. (2018). Imbalance of Mitochondrial Respiratory Chain Complexes in the Epidermis Induces Severe Skin Inflammation. The Journal of investigative dermatology 138(1), 132-140
• Lehtonen, J.M., Forsstrom, S., Bottani, E., Viscomi, C., Baris, O.R., Isoniemi, H., Hockerstedt, K., Osterlund, P., Hurme, M., Jylhava, J., et al. (2016). FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 87, 2290-2299.
• Baris O.R., Ederer S., Neuhaus J.F.G., von Kleist-Retzow J.C., Wunderlich C.M., Pal M., Wunderlich F.T., Peeva V., Zsurka G., Kunz W.S., et al. (2015). Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell Metabolism 21(5), 667-677.
• Kloepper, J.E.*, Baris, O.R.*, Reuter, K.*, Kobayashi, K., Weiland, D., Vidali, S., Tobin, D.J., Niemann, C., Wiesner, R.J., and Paus, R. (2015). Mitochondrial function in murine skin epithelium is crucial for hair follicle morphogenesis and epithelial-mesenchymal interactions. The Journal of investigative dermatology 135, 679-689. (* = Equal contribution)
• Neuhaus, J.F.*, Baris, O.R.*, Hess, S., Moser, N., Schroder, H., Chinta, S.J., Andersen, J.K., Kloppenburg, P., and Wiesner, R.J. (2014). Catecholamine metabolism drives generation of mitochondrial DNA deletions in dopaminergic neurons. Brain 137, 354-365. (* = Equal contribution)

Collaborations

• Rudolf J. Wiesner (Köln, Germany)
• Dirk Mielenz (Erlangen, Germany)
• Arnaud Mourier (Bordeaux, France)

Acknowledgements

This project is funded by:

            University of Angers (Project INGEMICA, 2 years funding)

            University Bretagne Loire (Salary Caroline Silveira Martinez)