BackgroundAlzheimer’s disease (AD) is the most common form of dementia, and it affects more women than men. Mitochondrial dysfunction (MD) plays a key role in AD, and it is detectable at an early stage of the degenerative process in peripheral tissues, such as peripheral mononuclear blood cells (PBMCs). However, whether these changes are also reflected in cerebral energy metabolism and whether sex-specific differences in mitochondrial function occur are not clear. Therefore, we estimated the correlation between mitochondrial function in PBMCs and brain energy metabolites and examined sex-specific differences in healthy participants to elucidate these issues.MethodsThe current pilot study included 9 male and 15 female healthy adults (mean age 30.8 ± 7.1 years). Respiration and activity of mitochondrial respiratory complexes were measured using a Clarke-electrode (Oxygraph-2k system), and adenosine triphosphate (ATP) levels were determined using a bioluminescence-based assay in isolated PBMCs. Citrate synthase activity as a mitochondrial marker was measured using a photometric assay. Concentrations of brain energy metabolites were quantified in the same individuals using 1H-magnetic resonance spectroscopy (MRS).ResultsWe detected sex-associated differences in mitochondrial function. Mitochondrial complexes I, I+II, and IV and uncoupled respiration and electron transport system (ETS) capacity in PBMCs isolated from blood samples of females were significantly (p < 0.05; p < 0.01) higher compared to males. ATP levels in the PBMCs of female participants were approximately 10% higher compared to males. Citrate synthase (CS) activity, a marker of mitochondrial content, was significantly (p < 0.05) higher in females compared to males. Sex-associated differences were also found for brain metabolites. The N-acetylaspartate (NAA) concentration was significantly higher in female participants compared to males in targeted regions. This difference was observed in white matter (WM) and an area with a high percentage (> 50%) of gray matter (GM) (p < 0.05; p < 0.01). The effect sizes indicated a strong influence of sex on these parameters. Sex-associated differences were found in PBMCs and brain, but the determined parameters were not significantly correlated.ConclusionsOur study revealed sex-associated differences in mitochondrial function in healthy participants. The underlying mechanisms must be elucidated in more detail, but our study suggests that mitochondrial function in PBMCs is a feasible surrogate marker to detect differences in mitochondrial function and energy metabolism in humans and it underscores the necessity of sex-specific approaches in therapies that target mitochondrial dysfunction.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0193-7) contains supplementary material, which is available to authorized users.

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Introduction Mitochondria supply cellular energy and are key regulators of intrinsic cell death and consequently affect longevity. The nematode Caenorhabditis elegans is frequently used for lifespan assays. Using paraquat (PQ) as a generator of reactive oxygen species, we here describe its effects on the acceleration of aging and the associated dysfunctions at the level of mitochondria. Methods Nematodes were incubated with various concentrations of paraquat in a heat-stress resistance assay (37°C) using nucleic staining. The most effective concentration was validated under physiological conditions, and chemotaxis was assayed. Mitochondrial membrane potential (ΔΨm) was measured using rhodamine 123, and activity of respiratory chain complexes determined using a Clark-type electrode in isolated mitochondria. Energetic metabolites in the form of pyruvate, lactate, and ATP were determined using commercial kits. Mitochondrial integrity and structure was investigated using transmission electron microscopy. Live imaging after staining with fluorescent dyes was used to measure mitochondrial and cytosolic ROS. Expression of longevity- and mitogenesis-related genes were evaluated using qRT-PCR. Results PQ (5 mM) significantly increased ROS formation in nematodes and reduced the chemotaxis, the physiological lifespan, and the survival in assays for heat-stress resistance. The number of fragmented mitochondria significantly increased. The ∆Ψm, the activities of complexes I-IV of the mitochondrial respiratory chain, and the levels of pyruvate and lactate were significantly reduced, whereas ATP production was not affected. Transcript levels of genetic marker genes, atfs-1, atp-2, skn-1, and sir-2.1, were significantly upregulated after PQ incubation, which implicates a close connection between mitochondrial dysfunction and oxidative stress response. Expression levels of aak-2 and daf-16 were unchanged. Conclusion Using paraquat as a stressor, we here describe the association of oxidative stress, restricted energy metabolism, and reduced stress resistance and longevity in the nematode Caenorhabditis elegans making it a readily accessible in vivo model for mitochondrial dysfunction.

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer's disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

Brain aging is one of the major risk factors for the development of several neurodegenerative diseases. Therefore, mitochondrial dysfunction plays an important role in processes of both, brain aging and neurodegeneration. Aged mice including NMRI mice are established model organisms to study physiological and molecular mechanisms of brain aging. However, longitudinal data evaluated in one cohort are rare but are important to understand the aging process of the brain throughout life, especially since pathological changes early in life might pave the way to neurodegeneration in advanced age. To assess the longitudinal course of brain aging, we used a cohort of female NMRI mice and measured brain mitochondrial function, cognitive performance, and molecular markers every 6 months until mice reached the age of 24 months. Furthermore, we measured citrate synthase activity and respiration of isolated brain mitochondria. Mice at the age of three months served as young controls. At six months of age, mitochondria-related genes (complex IV, creb-1, β-AMPK, and Tfam) were significantly elevated. Brain ATP levels were significantly reduced at an age of 18 months while mitochondria respiration was already reduced in middle-aged mice which is in accordance with the monitored impairments in cognitive tests. mRNA expression of genes involved in mitochondrial biogenesis (cAMP response element-binding protein 1 (creb-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), nuclear respiratory factor-1 (Nrf-1), mitochondrial transcription factor A (Tfam), growth-associated protein 43 (GAP43), and synaptophysin 1 (SYP1)) and the antioxidative defense system (catalase (Cat) and superoxide dismutase 2 (SOD2)) was measured and showed significantly decreased expression patterns in the brain starting at an age of 18 months. BDNF expression reached, a maximum after 6 months. On the basis of longitudinal data, our results demonstrate a close connection between the age-related decline of cognitive performance, energy metabolism, and mitochondrial biogenesis during the physiological brain aging process.

In a systematic study of nucleon transfer reactions accompanied by Coulomb excitation we have bombarded 152Sm, 16~ and 232Th with 206,208pb beams at incident energies close to the Coulomb barrier. Particle-gamma coincidence techniques were used to identify excited states of reaction products populated through inelastic scattering and in nucleon transfer reactions. One-neutron stripping and pick-up reactions on 152Sm were observed leading to known states of the rotation aligned il 3/2-bands in 1538m and 15 l Sm" In the 16~ + 2o6,208pb systems no significant population of low lying states of product nuclei was found in the nucleon-transfer channels. Large cross sections were observed for one-and two-neutron pick-up from 232Th at an incident energy of 6.4 MeV/u. Around the grazing angle they are of the same order of magnitude as the cross section measured for inelastic scattering. The results are analyzed in the framework of semiclassical models. PACS: 25.70

The Mediterranean plant Silybum marianum L., commonly known as milk thistle, has been used for centuries to treat liver disorders. The flavonolignan silibinin represents a natural antioxidant and the main bioactive ingredient of silymarin (silybin), a standard extract of its seeds. Mitochondrial dysfunction and the associated generation of reactive oxygen/nitrogen species (ROS/RNS) are involved in the development of chronic liver and age-related neurodegenerative diseases. Silibinin A (SIL A) is one of two diastereomers found in silymarin and was used to evaluate the effects of silymarin on mitochondrial parameters including mitochondrial membrane potential and ATP production with and without sodium nitroprusside- (SNP-) induced nitrosative stress, oxidative phosphorylation, and citrate synthase activity in HepG2 and PC12 cells. Both cell lines were influenced by SIL A, but at different concentrations. SIL A significantly weakened nitrosative stress in both cell lines. Low concentrations not only maintained protective properties but also increased basal mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels. However, these effects could not be associated with oxidative phosphorylation. On the other side, high concentrations of SIL A significantly decreased MMP and ATP levels. Although SIL A did not provide a general improvement of the mitochondrial function, our findings show that SIL A protects against SNP-induced nitrosative stress at the level of mitochondria making it potentially beneficial against neurological disorders.

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