The photodynamic and direct actions of methylene blue on mitochondrial energy metabolism: A balance of the useful and harmful effects of this photosensitizer.

Autor: Klosowski EM; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: eduardomk8@hotmail.com., de Souza BTL; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: byathais@hotmail.com., Mito MS; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: m_s_mito@yahoo.com.br., Constantin RP; Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: rpconstantin@gmail.com., Mantovanelli GC; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: laine_mantovanelli@hotmail.com., Mewes JM; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: juliana.mewes@outlook.com., Bizerra PFV; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: paulo_veiga22@hotmail.com., Menezes PVMDC; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: pvmcmenezes@hotmail.com., Gilglioni EH; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: gilglioni@hotmail.com., Utsunomiya KS; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: karina.utsunomiya@gmail.com., Marchiosi R; Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: rmarchiosi@uem.br., Dos Santos WD; Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: wdsantos@uem.br., Filho OF; Department of Biochemistry, Laboratory of Plant Biochemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: oferrarese@uem.br., Caetano W; Department of Chemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: wcaetano@uem.br., Pereira PCS; Department of Chemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: paulocamver@gmail.com., Gonçalves RS; Department of Chemistry, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: rsgoncalves2@uem.br., Constantin J; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: jconstantin@uem.br., Ishii-Iwamoto EL; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: eliiwamoto@uem.br., Constantin RP; Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá, 87020-900, Paraná, Brazil. Electronic address: rpconstantin@uem.br.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2020 Jun; Vol. 153, pp. 34-53. Date of Electronic Publication: 2020 Apr 18.
DOI: 10.1016/j.freeradbiomed.2020.04.015
Abstrakt: According to the literature, methylene blue (MB) is a photosensitizer (PS) with a high affinity for mitochondria. Therefore, several studies have explored this feature to evaluate its photodynamic effects on the mitochondrial apoptotic pathway under normoxic conditions. We are aware only of limited reports regarding MB's photodynamic effects on mitochondrial energy metabolism, especially under hypoxic conditions. Thus, the purposes of this study were to determine the direct and photodynamic acute effects of MB on the energy metabolism of rat liver mitochondria under hypoxic conditions and its direct acute effects on several parameters linked to energy metabolism in the isolated perfused rat liver. MB presented a high affinity for mitochondria, irrespective of photostimulation or proton gradient formation. Upon photostimulation, MB demonstrated high in vitro oxidizing species generation ability. Consequently, MB damaged the mitochondrial macromolecules, as could be evidenced by the elevated levels of lipid peroxidation and protein carbonyls. In addition to generating a pro-oxidant environment, MB also led to a deficient antioxidant defence system, as indicated by the reduced glutathione (GSH) depletion. Bioenergetically, MB caused uncoupling of oxidative phosphorylation and led to photodynamic inactivation of complex I, complex II, and F 1 F O -ATP synthase complex, thus decreasing mitochondrial ATP generation. Contrary to what is expected for an ideal PS, MB displayed appreciable dark toxicity on mitochondrial energy metabolism. The results indicated that MB acted via at least three mechanisms: direct damage to the inner mitochondrial membrane; uncoupling of oxidative phosphorylation; and inhibition of electron transfer. Confirming the impairment of mitochondrial energy metabolism, MB also strongly inhibited mitochondrial ATP production. In the perfused rat liver, MB stimulated oxygen consumption, decreased the ATP/ADP ratio, inhibited gluconeogenesis and ureogenesis, and stimulated glycogenolysis, glycolysis, and ammoniagenesis, fully corroborating its uncoupling action in intact cells, as well. It can be concluded that even under hypoxic conditions, MB is a PS with potential for photodynamic effect-induced mitochondrial dysfunction. However, MB disrupts the mitochondrial energy metabolism even in the dark, causing energy-linked liver metabolic changes that could be harmful in specific circumstances.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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