Coenzyme Q deficiency triggers mitochondria degradation by mitophagy

Abstract

Coenzyme Q10 (CoQ) is a small lipophilic molecule critical for the transport of electrons from complexes I and II to complex III in the mitochondrial respiratory chain. CoQ deficiency is a rare human genetic condition that has been associated with a variety of clinical phenotypes. With the aim of elucidating how CoQ deficiency affects an organism, we have investigated the pathophysiologic processes present within fibroblasts derived from 4 patients with CoQ deficiency. Assays of cultured fibroblasts revealed decreased activities of complex II+III, complex III, and complex IV, reduced expression of mitochondrial proteins involved in oxidative phosphorylation, decreased mitochondrial membrane potential, increased production of reactive oxygen species (ROS), activation of mitochondrial permeability transition (MPT), and reduced growth rates. These abnormalities were partially restored by CoQ supplementation. Moreover, we demonstrate that CoQ deficient fibroblasts exhibited increased levels of lysosomal markers (beta-galactosidase, cathepsin, LC3, and Lyso Tracker), and enhanced expression of autophagic genes at both transcriptional and translational levels, indicating the presence of autophagy. Electron microscopy studies confirmed a massive degradation of the altered mitochondria by mitophagy. Autophagy in CoQ deficient fibroblasts was abolished by antioxidants or cyclosporin treatments suggesting that both ROS and MPT participate in this process. Furthermore, prevention of autophagy in CoQ deficient fibroblasts by 3-methyl adenine or wortmannin, as well as the induction of CoQ deficiency in cells lacking autophagy (by means of genetic knockout of the Atg5 gene in mouse embryonic fibroblasts) resulted in apoptotic cell death, suggesting a protective role of autophagy in CoQ deficiency.

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

“…Inconsistencies in clinical studies, including differences in methodology, outcome measures, dosages, duration of treatment, and drug combinations, make it difficult to formulate a clear picture of the effects of CoQ in patients with MERRF syndrome. Increased ROS production and oxidative stress is a common consequence of mitochondrial dysfunction and CoQ deficiency [20,29]. We identified a significant increase in ROS generation and H 2 O 2 content in MERRF fibroblasts, which could be ameliorated by CoQ treatment.…”

“…CoQ is the most widely used therapeutic agent in patients with mitochondrial disease because of its well-documented role in energy metabolism. The putative beneficial effects of CoQ supplementation include: enhanced electron transport and ATP production, antioxidant, regulation of redox signaling, stabilization of the mitochondrial permeability transition pore, protecting against autophagy, and apoptotic cell loss [20,28,29]. Overall, reports of the efficacy of CoQ treatment in mitochondrial disorders have been mixed.…”

“…Protein content was determined by the Lowry procedure [19]. CoQ levels in cultured fibroblasts and cybrids were measured as previously described [20].…”

“…Immunofluorescence microscopy was performed using SD methods as previously described [20]. Cover slips were analyzed using a fluorescence microscope (Leica DMRE, Leica Microsystems GmbH, Wetzlar, Germany).…”

“…Western blotting was performed using a standard protocol [20] and the Immun Star HRP detection kit (Bio-Rad Laboratories Inc., Hercules, CA).…”