Mitochondrial oxidative stress in senescence and age-associated cardiac diseases

Jeanne Mialet-Perez, Researcher CRCN INSERM

jeanne.perez @ inserm.fr (jeanne.perez @ inserm.fr)

jeanne.mialetperez @ univ-angers.fr (jeanne.mialetperez @ univ-angers.fr)

Keywords : oxidative stress, mitochondria, senescence, cardiac aging

State of the art and objectives 

Cardiac diseases are the main cause of death in western countries, with increased prevalence due to aging of the population. Mitochondrial dysfunction is chiefly at play in the development of age-associated chronic cardiac diseases such as heart failure, but also in some hereditary cardiomyopathies. We aim at better understanding how mitochondrial oxidative stress regulate the fundamental mechanisms involved in cardiac remodelling and dysfunction such as senescence, cell death, inflammation, hypertrophy and fibrosis. We are exploring the functions of different sources of ROS, such as monoamine oxidases (MAOs) in order to interfere with these pathways. Cells and preclinical models are used to test new therapeutic approaches that aim at restoring mitochondrial function in cardiac diseases. At the translational level, we are collaborating with the cardiology department to test the relevance of these signaling pathways in cohorts of patients recruited at Angers University Hospital.

Main results from the last 5 years

• Characterization of the senescence program in cardiomyocytes and stromal cells during cardiac aging
• Identification of monoamine oxidases as main sources of mitochondrial ROS in cardiomyocytes

• Characterization of monoamine oxidase oxygen-inert mutants with impaired generation of oxidative stress
• Identification of new signaling pathways linking mitochondrial oxidative stress to aldehyde toxicity in heart failure 

Main publications and patents from the 5 last years

• Brevet Européen: « Nanoparticles for treating or preventing a cardiomyopathy and anthracycline-cytotoxicity, and their administration as an aerosol » Déposé le 7 septembre 2021 sous le n°PCT/EP2021/074624.
• Santin Y, Resta J, Parini A and Mialet-Perez J. Monoamine oxidases in age-associated diseases: new perspectives for old enzymes. Ageing Res Rev (2021). Mar;66:101256. doi: 10.1016/j.arr.2021.101256.
• Giacinto Iacovino L, Manzella N, Resta J, Vanoni MA, Rotilio Laura, Pisani L, Edmondson DE, Parini A, Mattevi A, Mialet-Perez J, Binda C. Rational re-design of Monoamine Oxidase A into a dehydrogenase to probe ROS in cardiac ageing. ACS Chem Biol (2020). doi: 10.1021/acschembio.0c00366.
• Santin Y, Fazal L, Sainte-Marie Y, Sicard P, Maggiorani D, Tortosa F, Yücel Yücel Y, Teyssedre L, Rouquette J, Marcellin M, Vindis C, Shih JC, Lairez O, Burlet-Schiltz O, Parini A, Lezoualc’h F and Mialet-Perez J. Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic post-ischemic cardiac remodelling. Cell Death and Differentiation (2020). doi: 10.1038/s41418-019-0470-y. 8.0
• Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, Proctor C, Correia-Melo C, Victorelli S, Fielder E, Berlinguer-Palmini R, Owens A, Greaves L, Kolsky KL, Parini A, Douin-Echinard V, LeBrasseur NK, Arthur HM, Tual-Chalot S, Schafer MJ, Roos CM, Miller J, Robertson N, Mann J, Adams PD, Tchkonia T, Kirkland JL, Mialet-Perez J*, Richardson GD* & Passos JF*. Length-independent telomere damage drives cardiomyocyte senescence. EMBO J (2019). doi: 10.15252/embj.2018100492.
• Manzella N, Santin Y, Maggiorani D, Martini H, Douin-Echinard V, Passos JF, Lezoualc’h F, Binda C, Parini A and Mialet-Perez J. Monoamine oxidase-A is a novel driver of stress-induced premature senescence through inhibition of parkin-mediated mitophagy. Aging Cell (2018). doi: 10.1111/acel.12811.

Collaborations

• C. Binda, University of Pavia, Italy
• A. Meli, INSERM Phymedex Montpellier
• G. Vandecasteele, INSERM UMR-S1180, Orsay, France
• J. Passos, Mayo clinic, Rochester, USA
• M. Verelst, CNRS CEMES Toulouse

Acknowledgements for the financial supports

• Fédération Française de Cardiologie
• ANR, Agence Nationale pour la Recherche
• Région Pays de la Loire
• Université Angers
• Angers Loire Métropole