Coenzyme Q biosynthesis is a complex process occurring in both the cytosol and the mitochondrial matrix. The cytosolic pathway is shared with cholesterol biosynthesis through the mevalonate pathway, while the biosynthesis of the benzoquinone ring starts from p-hydroxybenzoic acid (4-HB), derived from tyrosine. A crucial step in the CoQ assembly is the insertion of the isoprenyl chain in the aromatic ring of 4-HB catalysed by 4-para-hydroxybenzoate: polyprenyl transferase (Coq2). We used 4-nitrobenzoic acid (4-NB) as a competitive inhibitor of Coq2 to induce CoQ depletion [1]. We found that CoQ depleted cells showed increased cholesterol levels, increased HIF-1α levels and a reduced intracellular oxygen tension in addition to the well-known effects associated with CoQ depletion (low respiratory capacity, low ATP content and high ROS production). The analysis of the chemical-physical state of the cellular membranes showed an increased membrane rigidity that, in our opinion, is responsible for the reduced oxygen uptake. Moreover, we found increased cytosolic NADH levels that contribute to the stabilization of the hypoxic factor HIF-1α, which is responsible for the rearrangement of cellular metabolic status that cannot be completely restored by CoQ10 supplementation. These findings could be relevant for clinical interest suggesting an explanation for the lack of effectiveness of CoQ10 supplementation therapy observed in a number of patients affected by primary CoQ10 deficiency syndrome. Moreover, our data provide new insights on the effect of CoQ10 depletion in cells and sheds light on the mechanisms that underlie CoQ10 deficiency syndrome pathogenesis.

Coenzyme Q10 depletion induces endogenous hypoxia in cultured cells

Liparulo, Irene
Primo
;
Bergamini, Christian;Wenping, Wang;Rizzardi, Nicola;Kurelac, Ivana;Gasparre, Giuseppe;Romana, Fato
2018

Abstract

Coenzyme Q biosynthesis is a complex process occurring in both the cytosol and the mitochondrial matrix. The cytosolic pathway is shared with cholesterol biosynthesis through the mevalonate pathway, while the biosynthesis of the benzoquinone ring starts from p-hydroxybenzoic acid (4-HB), derived from tyrosine. A crucial step in the CoQ assembly is the insertion of the isoprenyl chain in the aromatic ring of 4-HB catalysed by 4-para-hydroxybenzoate: polyprenyl transferase (Coq2). We used 4-nitrobenzoic acid (4-NB) as a competitive inhibitor of Coq2 to induce CoQ depletion [1]. We found that CoQ depleted cells showed increased cholesterol levels, increased HIF-1α levels and a reduced intracellular oxygen tension in addition to the well-known effects associated with CoQ depletion (low respiratory capacity, low ATP content and high ROS production). The analysis of the chemical-physical state of the cellular membranes showed an increased membrane rigidity that, in our opinion, is responsible for the reduced oxygen uptake. Moreover, we found increased cytosolic NADH levels that contribute to the stabilization of the hypoxic factor HIF-1α, which is responsible for the rearrangement of cellular metabolic status that cannot be completely restored by CoQ10 supplementation. These findings could be relevant for clinical interest suggesting an explanation for the lack of effectiveness of CoQ10 supplementation therapy observed in a number of patients affected by primary CoQ10 deficiency syndrome. Moreover, our data provide new insights on the effect of CoQ10 depletion in cells and sheds light on the mechanisms that underlie CoQ10 deficiency syndrome pathogenesis.
Biochimica et Biophysica Acta (BBA) - Bioenergetics
e15
1
Liparulo, Irene; Bergamini, Christian; Wenping, Wang; Masin, Luca; Rizzardi, Nicola; Kurelac, Ivana; Gasparre, Giuseppe; Bortolus, Marco; Romana, Fato
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/818698
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