PHYSIOPATHOLOGICAL INFLUENCE OF MITOCHONDRIAL GENOME INSTABILITY DURING AGING

Olivier Baris, CNRS principal investigator

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 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 explore the mechanisms involved in the maintenance and quality control of mtDNA, in order to unravel their fate during aging and determine whether they can be targeted by therapeutic approaches.

Main results

• 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).
• Demonstration that mtDNA alterations in muscle satellite cells are involved in the development of sarcopenia (Kimoloi et al., 2022, J Cachexia Sarcopenia Muscle)

People involved

• Actual members: Claudie Gabillard-Lefort (Post-doc); Mireille Wertheimer (Technician)
• Past members: Mélody Gosselin (MSc); Louis Pouteau (MSc) ; Caroline Silveira-Martinez (Post-doc) Théophile Thibault (PhD)

Main publications and patents from the 5 last years

• Gabillard-Lefort C, Thibault T, Lenaers G, Wiesner RJ, Mialet-Perez J, Baris OR. Heart of the matter: Mitochondrial dynamics and genome alterations in cardiac aging. Mech Ageing Dev. 2025 Apr;224:112044.

• Bureau J, Manero F, Baris O, Bodin A, Verny C, Chevrollier A, Lenaers G, Codron P. Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models. Brain Commun. 2024 Nov 13;6(6):fcae404.

• Le Dantec Y, Lenaers G, Baris OR, Chevrollier A, Khiati S. Therapy by trans-splicing of OPA1 pre-messenger RNAs for the treatment of diseases associated with OPA1 gene mutations. Patent WO2024068898A1. Link: https://patents.google.com/patent/WO2024068898A1/en

• Boix J, Knuever J, Niehoff N, Sen A, Pla-Martin D, Baris OR, Etich J, Brachvogel B, Kaul H, Isbrandt D, Soroka E, Bazzi H, Wenger RH, Giavalisco P, Wiesner RJ. Constitutive HIF-1α Expression in the Epidermis Fuels Proliferation and Is Essential for Effective Barrier Formation. J Invest Dermatol. 2024 Nov 22:S0022-202X(24)02951-8.

• Beucher L, Gabillard-Lefort C, Baris OR, Mialet-Perez J. Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases ? Redox Biol. 2024 Nov;77:103393.

• Gabillard-Lefort C, Mialet-Perez J, Lenaers G, Baris OR. Naked mole-rats: at the heart of it. Trends Mol Med. 2024 Oct;30(10):906-907.

• Lhuissier C, Desquiret-Dumas V, Girona A, Alban J, Faure J, Cassereau J, Codron P, Lenaers G, Baris OR, Gueguen N, Chevrollier A. Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission. iScience. 2024 Apr 24;27(5):109808.

• Kimoloi S, Sen A, Guenther S, Braun T, Brügmann T, Sasse P, Wiesner RJ, Pla-Martín D, Baris OR. Combined fibre atrophy and decreased muscle regeneration capacity driven by mitochondrial DNA alterations underlie the development of sarcopenia. J Cachexia Sarcopenia Muscle. 2022 Aug;13(4):2132-2145.

• Urbanczyk S, Baris OR, Hofmann J, Taudte RV, Guegen N, Golombek F, Castiglione K, Meng X, Bozec A, Thomas J, Weckwerth L, Mougiakakos D, Schulz SR, Schuh W, Schlötzer-Schrehardt U, Steinmetz TD, Brodesser S, Wiesner RJ, Mielenz D. Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle. Cell Rep. 2022 Jun 7;39(10):110912.

• Gueguen N, Baris O, Lenaers G, Reynier P, Spinazzi M. Secondary coenzyme Q deficiency in neurological disorders. Free Radic Biol Med. 2021 Mar;165:203-218.

Collaborations

• David Egron (Montpellier, France)
• Dirk Mielenz (Erlangen, Germany)
• Arnaud Mourier (Bordeaux, France)
• David Pla-Martin (Düsseldorf, Germany)
• Rudolf J. Wiesner (Köln, Germany)

Acknowledgements 

Projects funded by :

• Agence Nationale de la Recherche
• Association Française contre les Myopathies
• Région Pays de la Loire
• Université d’Angers