Abstract
Coenzyme Q10 (CoQ10) is an endogenous lipophilic quinone, ubiquitous in biological membranes and endowed with antioxidant and bioenergetic properties, both crucial to the aging process. In fact, coenzyme Q10 synthesis is known to decrease with age in different tissues including skin. Moreover, synthesis can be inhibited by 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors such as statins, that are widely used hypocholesterolemic drugs. They target a key enzymatic step along the mevalonate pathway, involved in the synthesis of both cholesterol and isoprenylated compounds including CoQ10.In the present study, we show that pharmacological CoQ10 deprivation at concentrations of statins > 10000 nM triggers intracellular oxidative stress, mitochondrial dysfunction and generates cell death in human dermal fibroblasts (HDF). On the contrary, at lower statin concentrations, cells and mainly mitochondria, are able to partially adapt and prevent oxidative imbalance and overt mitochondrial toxicity. Importantly, our data demonstrate that CoQ10 decrease promotes mitochondrial permeability transition and bioenergetic dysfunction leading to premature aging of human dermal fibroblasts in vitro.
Highlights
Coenzyme Q (CoQ10) is a lipophilic endogenous isoprenylated quinone widely distributed and conserved in living organisms
We show that pharmacological Coenzyme Q10 (CoQ10) deprivation at concentrations of statins > 10000 nM triggers intracellular oxidative stress, mitochondrial dysfunction and generates cell death in human dermal fibroblasts (HDF)
Our data demonstrate that CoQ10 decrease promotes mitochondrial permeability transition and bioenergetic dysfunction leading to premature aging of human dermal fibroblasts in vitro
Summary
Coenzyme Q (CoQ10) is a lipophilic endogenous isoprenylated quinone widely distributed and conserved in living organisms. C. plasma membrane CoQ10H2 has been shown to exert an anti-apoptotic effect by counteracting the release of ceramide from sphingomyelin, regulating the extracellularly-induced ceramide-dependent programmed cell death pathway [2]. Plasma membrane CoQ10H2 has been shown to exert an anti-apoptotic effect by counteracting the release of ceramide from sphingomyelin, regulating the extracellularly-induced ceramide-dependent programmed cell death pathway [2] In this respect, Plasma Membrane Reductive Systems (PMRS) play a major role in activating CoQ10 through enzymatic two electron reduction catalyzed by dehydrogenase enzymes, mainly NADH-cytochrome b5 reductase and NAD(P)H: quinone reductase 1 (NQO1). Plasma Membrane Reductive Systems (PMRS) play a major role in activating CoQ10 through enzymatic two electron reduction catalyzed by dehydrogenase enzymes, mainly NADH-cytochrome b5 reductase and NAD(P)H: quinone reductase 1 (NQO1) This activity is influenced by the aging process and by pro-oxidant stimuli that may decrease the activity of membrane CoQ10 reductive systems [3]. Recent studies have shown that over-expression of NQO1 in transgenic mice, was able to mimic the effects of CR by decreasing the levels of inflammation and neoplastic proliferation as well as enhancing bioenergetic activity [4]
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