Complex IV

Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-D: -aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II-III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.

Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40days). Results showed that CRS increased complex I-III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased.

Bipolar disorder (BD) is a mental illness associated with higher rates of suicide. The present study aims to investigate the brain mitochondrial respiratory chain activity in an animal model of mania induced by ouabain. Adult male Wistar rats received a single intracerebroventricular administration of ouabain (10-3 and 10-2 M) or vehicle. Locomotor activity was measured using the open field test. Mitochondrial respiratory chain activity was measured in the brain of rats 1 h and 7 days after ouabain administration. Our results showed that spontaneous locomotion was increased 1 h and 7 days after ouabain administration. Complexes I, III and IV activities were increased in the prefrontal cortex, hippocampus and striatum immediately after the administration of ouabain, at the concentration of 10-3 and 10-2 M. Moreover, complex II activity was increased only in the prefrontal cortex at the concentration of 10-2 M. On the other hand, no significant alterations were observed in complex I activity 7 days after ouabain administration. However, an increase in complexes II, III and IV activities was observed only in the prefrontal cortex at the concentration of 10-2 M. Our findings suggest an increase in the activities of mitochondrial respiratory chain in this model of mania. A possible explanation is that these findings occur as a rebound effect trying to compensate for a decrease of ATP deprivation in BD. The present findings suggest that this model may present good face validity and a limitation in construct validity.

Previous studies have demonstrated the beneficial effects of apple polyphenol (AP) intake on muscle endurance. Since mitochondria are critical for muscle endurance, we investigated mitochondrial enzyme activity, biogenesis, degradation and protein quality control. Twenty‐four Wistar rats were randomly fed a 5% AP diet (5% AP group, n = 8), a 0.5% AP diet (0.5% AP group, n = 8), or a control diet (control group, n = 8). After a 4‐week feeding period, the expression level of peroxisome proliferator‐activated receptor γ coactivator‐1α, a mitochondrial biosynthetic factor, did not increase, whereas that of transcription factor EB, another regulator of mitochondrial synthesis, significantly increased. Moreover, the mitochondrial count did not differ significantly between the groups. In contrast, mitophagy‐related protein levels were significantly increased. The enzymatic activities of mitochondrial respiratory chain complexes II, III and IV were significantly higher in the AP intake group than in the control group. We conclude that AP feeding increases the activity of respiratory chain complex enzymes in rat skeletal muscles. Moreover, mitochondrial biosynthesis and degradation may have increased in AP‐treated rats.

It has been described that using noninvasive exposure to 40-Hz white light LED reduces amyloid-beta, a peptide thought to initiate neurotoxic events in Alzheimer's disease (AD). However, the mechanisms remain to be identified. Since AD impairs mitochondrial potassium channels and respiratory chain activity, the objectives of the current study were to determine the effect of 40-Hz white light LED on structure-function of mitoKATP channel and brain mitochondrial respiratory chain activity, production of reactive oxygen species (ROS), and ΔΨm in AD. Single mitoKATP channel was considered using a channel incorporated into the bilayer lipid membrane and expression of mitoKATP-Kir6.1 subunit as a pore-forming subunit of the channel was determined using a western blot analysis in Aβ1-42 toxicity and light-treated rats. Our results indicated a severe decrease in mito-KATP channel permeation and Kir6.1 subunit expression coming from the Aβ1-42-induced neurotoxicity. Furthermore, we found that Aβ1-42-induced neurotoxicity decreased activities of complexes I and IV and increased ROS production and ΔΨm. Surprisingly, light therapy increased channel permeation and mitoKATP-Kir6.1 subunit expression. Noninvasive 40-Hz white light LED treatment also increased activities of complexes I and IV and decreased ROS production and ΔΨm up to ~ 70%. Here, we report that brain mito-KATP channel and respiratory chain are, at least in part, novel targets of 40-Hz white light LED therapy in AD.

Impact of iron oxide nanoparticles on brain, heart, lung, liver and kidneys mitochondrial respiratory chain complexes activities and coupling

Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury

Depressive disorders, including major depression, are serious and disabling for affected patients. Although the neurobiological understanding of major depressive disorder focuses mainly on the monoamine hypothesis, the exact pathophysiology of depression is not fully understood. Animals received daily intra-peritoneal injections of paroxetine (10 mg/kg), nortriptyline (15 mg/kg) or venlafaxine (10 mg/kg) in 1.0 ml/kg volume for 15 days. Twelve hours after the last injection, the rats were killed by decapitation, where the brain was removed and homogenised. The activities of mitochondrial respiratory chain complexes in different brain structures were measured. We first verified that chronic administration of paroxetine increased complex I activity in prefrontal cortex, hippocampus, striatum and cerebral cortex. In addition, complex II activity was increased by the same drug in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. Furthermore, chronic administration of nortriptyline increased complex II activity in hippocampus and striatum and complex IV activity in prefrontal cortex, striatum and cerebral cortex. Finally, chronic administration of venlafaxine increased complex II activity in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. On the basis of the present findings, it is tempting to speculate that an increase in brain energy metabolism by the antidepressant paroxetine, nortriptyline and venlafaxine could play a role in the mechanism of action of these drugs. These data corroborate with other studies suggesting that some antidepressants modulate brain energy metabolism.

Mitochondrial respiratory chain activity in the human brain as a function of age

Coenzyme Q–dependent mitochondrial respiratory chain activity in granulosa cells is reduced with aging

Mussel species of the genus Mytilus possess an unusual system of mitochondrial DNA (mtDNA) transmission termed doubly uniparental inheritance. They are characterized by the presence of two highly divergent gender-associated mtDNA genomes (often with>20 and>10% divergences in DNA and amino acid sequences, respectively) that are inherited either maternally (F mtDNA) or paternally (M mtDNA). Females are typically homoplasmic for the F mtDNA and males are heteroplasmic with the F mtDNA being most common in all tissues except the gonad that is dominated by the M mtDNA. Collectively, males are polymorphic for two classes of M mtDNAs known as the "standard male" and "recently masculinized" M types (SM and RM, respectively). The coding portions of the RM mtDNA genome differ from the SM mtDNA by as much as the maternally inherited F mtDNA genome differs from the SM type. Because the SM and RM types exhibit considerable amino acid sequence divergence, we hypothesized that these differences could affect mitochondrial respiratory chain complex enzyme activities. To test this hypothesis, the activity of the major mitochondrial respiratory chain complexes (complexes II, I+III and IV) as well as the activity of citrate synthase were measured on gonad samples from males containing either the SM or RM mtDNA. Our data demonstrate that the mitochondrial subunits encoded by the RM mtDNA are associated with higher enzymatic activities than the gene products of the SM mtDNA.

Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo. In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. In order to address the question of a putative role of mitochondrial dysfunction in the pathogenesis of ALS, we studied the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain enzyme activities in spinal cords of ALS patients and in control subjects without neuropathologic abnormalities. Using a "double PCR and digestion" technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, we found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls. No large-scale rearrangements were found, but the amount of mtDNA, measured by Southern blot, was significantly lower in the ALS samples. This reduction correlated well with a decrease of citrate synthase (CS) activity, a mitochondrial marker, as were the activities of respiratory chain complexes I + III, II + III, and IV, suggesting a loss of mitochondria in ALS spinal cords.

Mitochondrial respiratory chain enzyme activities were determined by spectrophotometric enzyme assay in lymphocytes of 100 patients with acute myocardial infarction. A significant decrease in the activity of complexes II–III and IV and an increase in the activity of complex I of the respiratory chain were found. According to the correlation analysis, the feedback of troponin T and I concentrations in the serum and the activity of complex IV of the respiratory chain was detected. A decrease in the activity of the IV complex of the mitochondrial lymphocyte respiratory chain below 2.87 IU/g of protein indicates an increased level of clinical risk in patients with acute myocardial infarction.

Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development. To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene. Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed. In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N(55e11) in Drosophila decreases the activity of mitochondrial respiratory complexes I and V. Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.