Coenzyme Q10 deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons

Topic:

Other

Poster Number: 333 T

Author(s):

Alba Pesini, PhD, Columbia University, New York, US, Eliana Barriocanal-Casado, Columbia University, New York, US, Giacomo Monzio Compagnoni, University of Milan, Milan, Italy, Agustin Hidalgo-Gutierrez, Columbia University, New York, US, Mohammed Bakkali, University of Granada, Granada, Spain, Yashpal S Chhonker, University of Nebraska Medical Center, Nebraska, US, Giulio Kleiner, Columbia University, New York, US / Icahn School of Medicine at Mount Sinai, New York, US, Delfina Larrea, Columbia University, New York, US, Saba Tadesse, Columbia University, New York, US, Daryl J Murry, University of Nebraska Medical Center, Nebraska, US, Alessio Di Fonzo, University of Milan, Milan, Italy, Estela Area-Gomez, Centro de Investigaciones Biológicas Margarita Salas, CSIC, Madrid, Spain, Catarina M Quinzii, Columbia University, New York, US

Background: Coenzyme Q10 (CoQ10) is an antioxidant and a critical component of the
mitochondrial respiratory chain. CoQ10 deficiencies cause a variety of clinical syndromes, often involving encephalopathies, including cerebellar ataxia. The heterogeneity of clinical manifestations, the tissue-specificity, and the variable response to therapy of CoQ10 deficiency imply different pathomechanisms at play, reflecting CoQ10 involvement in several other biological processes beside the oxidative phosphorylation. One such process is cholesterol homeostasis, since CoQ10 is synthetized through the mevalonate pathway, which also produces cholesterol, and the two biosynthetic pathways are co-regulated.
Objective: To investigate the interplay between CoQ10 biosynthesis and lipid metabolism, including cholesterol homeostasis, and the role of its dysfunction in the context of CoQ10 deficient encephalopathies.
Results: To elucidate this connection, we have investigated lipid metabolism in human iPSCs-derived neurons with primary and secondary CoQ10 deficiencies, and in SH-SY5Y neurons after pharmacological manipulation of the mevalonate pathway at different levels. We show that CoQ10 deficiency causes alterations in lipid metabolism, including cholesterol homeostasis, fatty acids oxidation, phospholipids and sphingolipids synthesis in neurons. These alterations vary, depending on whether CoQ10 deficiency is primary or secondary. Our results imply that CoQ10 deficiencies can induce pathology via alterations in the modulation of lipid homeostasis and in the composition of cellular membranes.
Conclusion: These findings provide further understanding of the mechanisms underlying CoQ10 deficiency and their connection with lipid metabolism, pointing to potential novel therapeutic targets.