Melatonin in Mitochondrial Dysfunction and Related Disorders

Table 1

Melatonin activity in bioenergetic functions: evidence from in vitro and in vivo studies.

Animal model studies (in vitro and in vivo)	Pretreatment	Posttreatment with melatonin	Reference(s)
Ruthenium red-effect on ETC system	Inhibition of complex I and IV and impairment of ATP synthesis	Counteracted ruthenium red’s inhibitory action complex I and IV	[15]
t-BHP treated mitochondrial preparations	Depletion of mitochondrial GSH; inhibition of GPx and GRd activities	Prevented the oxidation of GSH to GSSG, restored GPx and GRd back to normal	[14]
MPTP effect on isolated striatal synaptosomes and liver mitochondria	Inhibition of ETC complex I	Prevented MPTP-induced inhibition of complex I	[160]
SAMP-8 mice	Elevated lipid peroxidation products	Reduced lipid peroxidation	[122]
LPS-injected rats	Increased mitochondrial NOS. NO decreased ETC complex I and IV	Decreased NO production and counteracted LPS-induced inhibition of complex I an IV	[146]
Ischemia-reperfusion effect on mitochondria	Opens mtPT pores and destroys cardiolipin in mitochondria	Inhibits mtPT pore opening and preserves the structural complex of cardiolipin in mitochondria	[140]
Mitochondria from heart and diaphragm muscle of SAMP-8 mice	Increased LPO; decrease in GSH levels and GPx and GRd activities	Counteracted age-dependent increase in LPO and reduction of GSH, GPx, and GRd	[125]
Skeletal muscle of septic wild-type (iNOS^+/+) and iNOS knockout (iNOS^−/−) mice	Increase of mt iNOS and NO levels, increase of lipid peroxidation products, decrease of GSH levels and of GPx and GRd activities	Decreased mt iNOS and NO levels, counteracted reduction of GSH, GPx and GRd	[148]
Diaphragmatic muscle of septic wild type (iNOS^+/+) and iNOS knockout (iNOS^−/−) mice	Increase of mt iNOS and NO levels, reduction of GSH and of GPx and GRd activities	Decreased mt iNOS and NO levels; counteracted reduction of GSH, GPx, and GRd	[149]
Mitochondria from rat liver	Normal ETC function	Melatonin treatment decreased Krebs’s cycle substrate-induced respiration.	[108]
Heart and diaphragmatic muscle of SAMP-8 mice	Decreased levels of GSH and of GPx and GRd activities, increased lipid peroxidation	Increased GSH levels and GPx and GRd activities; decreased lipid peroxidation products	[126]
Diaphragmatic muscle of SAMP-8 mice-effect of aging	Decrease of GSH and GPx, GRd, increase in lipid peroxidation	Counteracted age-dependent decrease in GSH, GPx, and GRd Normalized lipid peroxidation	[127]
Mitochondria from liver of normal mice	Normal function of ETC complexes; opening of mtPT pores after oxidative stress	Increased complex I, III, and IV; closing of the mtPT pores opened by oxidative stress	[18]
t-BHP effect on mitochondria of skeletal muscle	Opening of mtPT and death of myotubules	Prevented t-BHP-induced opening of mtPT pores and swelling of mitochondria	[109]
MPTP effect on mitochondria of neurons in substantia nigra of mice	Increased mt iNOS; increased oxidative stress	Counteracted MPTP-induced increase of iNOS in substantia nigra and reduced the oxidative stress	[161]
Effect of ischemia-reperfusion on mitochondria	Opening of mtPT pores and oxidation of cardiolipin	Inhibited mtPT pores and cardiolipin oxidation	[110, 143]
Effect of Aβ on hippocampal neurons	Inhibition of ETC; reduced ATP levels	Attenuated Aβ-induced inhibition of respiratory complexes; restored ATP levels	[187]

Abbreviations used: Aβ: β amyloid; ETC: electron transport chain; GPx: glutathione peroxidase; GRd: glutathione reductase; GSH: reduced glutathione; GSSG: oxidized glutathione; iNOS: inducible nitric oxide synthase; LPS: lipopolysaccharide; MPTP: 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine; mt iNOS: mitochondrial inducible nitric oxide synthase; mtPT: mitochondrial permeability transition; NO: nitric oxide; SAMP-8 mice: senescence accelerated mouse; t-BHP: t-butyl hydroperoxide.