Stimulation of cholesterol biosynthesis in mitochondrial complex I-deficiency lowers reductive stress and improves motor function and survival in mice

Tom J.J Schirris,Sergio Rossell,Ria De Haas,Sanne J.C.M Frambach,Charlotte A Hoogstraten,G Herma Renkema,Julien D Beyrath,Peter H.G.M Willems,Martijn A Huynen,Jan A.M Smeitink,Frans G.M Russel,Richard A Notebaart

doi:10.1016/j.bbadis.2020.166062

Abstract

The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders. Here, we present a comprehensive human metabolic network model of genetically characterized CI-deficient patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, and utilization can counterbalance the surplus of reducing equivalents in patient-derived fibroblasts, as these pathways consume considerable amounts of NAD(P)H. We show that fibrates attenuated increased NAD(P)H levels and improved CI-deficient fibroblast growth by stimulating the production of cholesterol via enhancement of its cellular efflux. In CI-deficient (Ndufs4−/−) mice, fibrate treatment resulted in prolonged survival and improved motor function, which was accompanied by an increased cholesterol efflux from peritoneal macrophages. Our results shine a new light on the use of compensatory biological pathways in mitochondrial dysfunction, which may lead to novel therapeutic interventions for mitochondrial diseases for which currently no cure exists.

Highlights

ATP, the main cellular energy source, is predominantly produced by the mitochondrial oxidative phosphorylation (OXPHOS) system, which consists of five enzyme complexes and two electron carriers
In line with a compensatory role for the cholesterol biosynthesis, utilization and efflux expression of various genes of these pathways was increased Complex I (CI)-deficient patients compared to healthy controls (Supplementary Fig. A.1A–C)
The beneficial effects of fibrates in CI-deficient patient fibroblasts is in agreement with the previously observed favorable effects of bezafibrate in several mouse models of cytochrome c oxidase (COX) or CIV defi ciency, as reviewed previously [44,49], and short-term beneficial effects recently observed after bezafibrate treatment of patients with mito chondrial myopathies [47]

Summary

Introduction

ATP, the main cellular energy source, is predominantly produced by the mitochondrial oxidative phosphorylation (OXPHOS) system, which consists of five enzyme complexes and two electron carriers. OXPHOS dysfunction is the primary cause of many inherited mitochondrial dis orders and has been associated with more common diseases, including cancer, heart failure and neurodegeneration [1,2,3,4]. A deficient activity of this complex is the underlying cause of many mitochondrial disorders, including Leigh syndrome [5,6]. The often early fatal disease typically manifests within the first two years of life and is characterized by elevated blood and cerebrospinal fluid lactate concentrations. At the cellar level ATP production is reduced and reactive oxygen species (ROS) and NAD(P)H levels are increased [6].

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Results

Conclusion