Cecatto 2019 Toxicol In Vitro
|Cecatto C, Amaral AU, Roginski AC, Castilho RF, Wajner M (2019) Impairment of mitochondrial bioenergetics and permeability transition induction caused by major long-chain fatty acids accumulating in VLCAD deficiency in skeletal muscle as potential pathomechanisms of myopathy. Toxicol In Vitro 62:104665.|
Abstract: cis-5-Tetradecenoic (cis-5) and myristic (Myr) acids predominantly accumulate in patients affected by very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. They commonly manifest myopathy with muscular pain and rhabdomyolysis, whose underlying mechanisms are poorly known. Thus, in the present study we investigated the effects of cis-5 and Myr on mitochondrial bioenergetics and Ca2+ homeostasis in rat skeletal muscle. cis-5 and Myr decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration, especially when mitochondria were supported by NADH-linked as compared to FADH2-linked substrates. In contrast, these fatty acids increased resting respiration (state 4). Similar effects were observed in skeletal muscle fibers therefore validating the data obtained with isolated mitochondria. Furthermore, cis-5 and Myr markedly decreased mitochondrial membrane potential and Ca2+ retention capacity that were avoided by cyclosporin A plus ADP and ruthenium red, indicating that cis-5 and Myr induce mitochondrial permeability transition (MPT). Finally, docosanoic acid did not disturb mitochondrial homeostasis, indicating selective effects for Myr and cis-5. Taken together, our findings indicate that major long-chain fatty acids accumulating in VLCAD deficiency behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and MPT inducers. It is presumed that these pathomechanisms contribute to the muscular symptoms and rhabdomyolysis observed in patients affected by VLCAD deficiency.
Copyright © 2019 Elsevier Ltd. All rights reserved.
• Keywords: Ca(2+) homeostasis, Mitochondrial bioenergetics, Myopathy, Myristic acid, VLCAD deficiency, cis-5-tetradecenoic acid • Bioblast editor: Plangger M • O2k-Network Lab: BR Porto Alegre Souza DOG
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Inherited, Myopathy, Other Stress:Permeability transition Organism: Rat Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue, Isolated mitochondria
Regulation: Calcium, mt-Membrane potential, Fatty acid Coupling state: LEAK, OXPHOS, ET Pathway: N, S HRR: Oxygraph-2k