Mitochondrial complex I deficiencies: From diagnosis to therapeutic screening

Valérie Desquiret-Dumas                                      Naïg Gueguen

                   hospital engineer                                                      hospital engineer

              VaDesquiret @ chu-angers.fr (VaDesquiret @ chu-angers.fr)                                        NaGueguen @ chu-angers.fr (NaGueguen @ chu-angers.fr)

State of the art and objectives

Involved in the biochemical and molecular diagnosis of mitochondrial disorders in the Department of Biochemistry and Genetics and the reference center for mitochondrial diseases at the University Hospital of Angers, we develop a translational research focused on complex I (CI) deficiencies and metabolic reprogramming.

Among mitochondrial diseases, complex I (CI) deficiency is the most commonly found in up to 30% of patients, leading to drastic energetic impairment. In order to adapt their metabolism to environmental conditions, cells must possess a metabolic flexibility to rewire energetic metabolic pathways according to substrate or oxygen availability or oxidative stress. We demonstrated that this metabolic flexibility was impeded in CI patients and that the metabolic rewiring set up to cope with energetic impairment mainly relies on a correct assembly of all the respiratory chain complex subunits.

With the goal of identifying new diagnosis biomarkers and therapeutic targets, we take advantage of a large cohort of patient fibroblasts suffering from CI deficiencies to study the link between the structure and the function mitochondrial complex I and the metabolic adaptations set up to cope with energetic impairment paying a particular attention on redox (NAD+/NADH) and energetic (ATP/ADP) ratios. With the support of the Fondation Maladies Rares we are now performing a pharmacological screening that can target the identified defects in order to provide new therapeutic alternatives in disease without curative treatments nowadays.

Main results from the last 5 years

• We have shed light on the crucial role of mitochondrial complex I, by the regulation of the NAD+/NADH ratio, in mitochondrial response to Resveratrol treatment (Desquiret-Dumas et al., 2013, Gueguen et al., 2015).
• We have demonstrated that a complex I misassembly was responsible for oxidative stress and energetic impairment in patient fibroblasts (Leman et al., 2015).
• We have identified the level of complex I assembly as a determinant parameter of the metabolic orientation of complex I patient cells (Desquiret-Dumas et al., in revision).
• We have evidenced a signaling pathway linking ROS overproduction and deficient pyruvate channeling to mitochondria, consequently leading to an increase in glycolytic metabolism in complex I patient cells (Desquiret-Dumas et al., in revision).
• This characterization has enabled us to identify new pharmacological molecules which could improve mitochondrial metabolism in patient cells. These ones are currently being tested for biological validation on our wide complex I patient cells cohort.

People involved

• Desquiret-Dumas Valérie, Hospital Engineer, PhD
• Gueguen Naïg, Hospital Engineer, PhD

Main publications and patents from the 5 last years    

• Geffroy G, Benyahia R, Frey S, Desquiret-Dumas V, Gueguen N, Bris C, Belal S, Inisan A, Renaud A, Chevrollier A, Henrion D, Bonneau D, Letournel F, Lenaers G, Reynier P, Procaccio V. The accumulation of assembly intermediates of the mitochondrial complex I matrix arm is reduced by limiting glucose uptake in a neuronal-like model of MELAS syndrome. Biochim Biophys Acta Mol B asis Dis. 2018 May;1864(5 Pt A):1596-1608.
• Frey S, Geffroy G, Desquiret-Dumas V, Gueguen N, Bris C, Belal S, Amati-Bonneau P, Chevrollier A, Barth M, Henrion D, Lenaers G, Bonneau D, Reynier P, Procaccio V. The addition of ketone bodies alleviates mitochondrial dysfunction by restoring complex I assembly in a MELAS cellular model. Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):284-291.
• Gueguen N*, Desquiret-Dumas V*, Leman G, Chupin S, Baron S, Nivet-Antoine V, Vessières E, Ayer A, Henrion D, Lenaers G, Reynier P, Procaccio V. Resveratrol Directly Binds to Mitochondrial Complex I and Increases Oxidative Stress in Brain Mitochondria of Aged Mice. PLoS One. 2015 Dec 18;10(12):e0144290. *cofirst authors
• Leman G, Gueguen N, Desquiret-Dumas V, Kane MS, Wettervald C, Chupin S, Chevrollier A, Lebre AS, Bonnefont JP, Barth M, Amati-Bonneau P, Verny C, Henrion D, Bonneau D, Reynier P, Procaccio V. Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency. Int J Biochem Cell Biol. 2015 Aug;65:91-103.
• Desquiret-Dumas V*, Gueguen N*, Leman G, Baron S, Nivet-Antoine V, Chupin S, Chevrollier A, Vessières E, Ayer A, Ferré M, Bonneau D, Henrion D, Reynier P, Procaccio V. Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. J Biol Chem. 2013 Dec 20;288(51):36662-75. *cofirst authors

Acknowledgements for the financial supports

Fondations Maladies Rares:  Screening of pharmacological molecules to restore oxidative metabolism in mitochondrial complex I mutated patients.

Patient associations :

“Fondation VISIO”, “Ouvrir les Yeux”, “Union Nationale des Aveugles et Déficients Visuels” “Association contre les Maladies Mitochondriales”, “Retina France”, “Kjer France”,