Dichloroacetate as a metabolic modulator of heart mitochondrial proteome under conditions of reduced oxygen utilization

• Published in: Scientific reports 2022-09, Vol.12 (1), p.16348-16, Article 16348
• Main Authors: Andelova, Natalia, Waczulikova, Iveta, Kunstek, Lukas, Talian, Ivan, Ravingerova, Tanya, Jasova, Magdalena, Suty, Simon, Ferko, Miroslav
• Format: Article
• Language: English
• Subjects: 631/443; 631/443/319/333; Acetates; Amines; Animals; Antioxidants; Calcium; Calcium (mitochondrial); Calcium influx; Calcium permeability; Diabetes; Diabetes mellitus; Dichloroacetic acid; Flavin; Flavins; Fluorescence spectroscopy; Humanities and Social Sciences; Hydrocarbons, Chlorinated; Membrane permeability; Membrane potential; Membrane proteins; Mitochondria; Mitochondrial Permeability Transition Pore; multidisciplinary; Myocardium; Oxidoreductases; Oxygen; Peroxide reductase; Peroxides; Protein interaction; Proteins; Proteome; Proteomes; Proteomics; Reactive Oxygen Species; Science; Science (multidisciplinary); Signal transduction; Streptozocin; Thioredoxin; Thioredoxins
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-20696-5

Myocardial compensatory mechanisms stimulated by reduced oxygen utilization caused by streptozotocin-induced diabetes mellitus (DM) and treated with dichloroacetate (DCA) are presumably associated with the regulation of mitochondria. We aimed to promote the understanding of key signaling pathways and identify effectors involved in signal transduction. Proteomic analysis and fluorescence spectroscopy measurements revealed significantly decreased membrane potential and upregulated protein amine oxidase [flavin-containing] A (AOFA) in DM mitochondria, indicative of oxidative damage. DCA in diabetic animals (DM + DCA) downregulated AOFA, increased membrane potential, and stimulated thioredoxin-dependent peroxide reductase, a protein with antioxidant function. Furthermore, the DM condition was associated with mitochondrial resistance to calcium overload through mitochondrial permeability transition pores (mPTPs) regulation, despite an increased protein level of voltage-dependent anion-selective protein (VDAC1). In contrast, DM + DCA influenced ROS levels and downregulated VDAC1 and VDAC3 when compared to DM alone. The diabetic myocardium showed an identical pattern of mPTP protein interactions as in the control group, but the interactions were attenuated. Characterization of the combined effect of DM + DCA is a novel finding showing that DCA acted as an effector of VDAC protein interactions, calcium uptake regulation, and ROS production. Overall, DM and DCA did not exhibit an additive effect, but an individual cardioprotective pathway.