Immune activation is generally acknowledged to be costly. These costs are frequently assumed to result from trade-offs arising due to the reallocation of resources from other life-history traits to be invested in immunity. Here, I investigated the energetic basis of the costs associated with immune activation in Drosophila melanogaster. I found that immune activation significantly reduced fly fecundity (45%) and also caused a decline in metabolic rate (6%) but had no effect on body weight. To understand the factors behind reduced fecundity and metabolic rate I measured feeding and found that food intake was reduced by almost 31% in immune-challenged D. melanogaster. These findings suggest that fecundity costs of immune activation result not from the commonly accepted resource reallocation hypothesis but probably because resource acquisition is impaired during immune responses. The individuals of any animal population generally vary greatly in their ability to resist infectious disease. This variation arises due to both environmental heterogeneity and genetic diversity. Genetic variation in disease susceptibility has generally been considered to lie in the nuclear genome. Here, for the first time, I explored the influence of mitochondrial genetic (mtDNA) variation on disease susceptibility. I crossed 22 mitochondrial haplotypes onto a single nuclear genome and also studied epistasis interactions between mitochondrial and nuclear genomes (mitonuclear epistasis) by crossing five haplotypes onto five different genetic backgrounds. I found that fly susceptibility to Serratia marcescens was influenced significantly by mtDNA allelic variation. Furthermore, the effect of mitonuclear epistasis on fly susceptibility to S. marcescens was twice as great as the individual effects of either mitochondrial or nuclear genome. However, susceptibility to Beauveria bassiana was not affected by mtDNA allelic variation. These findings suggest the mitochondrial genome may play an important role in host-parasite coevolution. The Mother’s Curse hypothesis suggests that sex-specific selection due to maternal mitochondrial inheritance means that mitochondria are poorly adapted to function in males, resulting in impaired male fitness. Mother’s Curse effects have previously only been studied for two phenotypic traits (sperm-infertility and ageing) and their generality for broader life-history has not been explored. I investigated the impact of mtDNA allelic variation on 10 phenotypic traits and tested whether the patterns of phenotypic variation in males and females conformed to the expectations of the Mother’s Curse hypothesis. I found that seven of the 10 traits were significantly influenced by mtDNA allelic variation. However, there was no evidence that the effects of this variation differed between males and females. I therefore concluded that Mother’s Curse is unlikely to be a general phenomenon, nor to provide a general explanation for sexual dimorphism in life-history traits. Overall, this thesis explored the impacts of immunity costs, mitochondrial genetic variation, mitonuclear epistasis and sex-specific mitochondrial selection on D. melanogaster life-history.

This study investigates the connection between different pathophysiological processes in mitochondria and psychopathological symptoms in patients with bipolar disorder. Changes in activity of selected components of the respiratory chain and overall respiratory rate of mitochondria were analyzed in patients with bipolar disorder when compared to healthy controls. Diagnostic scales and questionnaires, high-resolution respirometry, radiochemical and spectroscopic methods were used. 37 patients with a diagnosis of bipolar disorder (F31) and 21 healthy volunteers were involved in the study. Statistical analysis included the methods of parametric and nonparametric analysis, factor analysis, one-way analysis of variance and linear regression analysis. Obtained results revealed that cellular energetics plays a great role in the pathophysiology of bipolar disorder. There was a mild difference between different mitochondrial enzymes activity in patients within manic phases and depressive phases of the disease. Changes in mitochondrial respiration in patients with BD as compared to healthy controls were also shown. Mitochondrial respiration indexes for patients with BD in remission as compared to healthy controls were altered in accordance with the previous phase of the disease. Association between the...

Indiana University-Purdue University Indianapolis (IUPUI) / The etiology of many neurodegenerative diseases is unknown, but a number of studies indicate that a combination of both genetic and environmental factors contribute to the progression of disease. Exposure to environmental metals, such as Mn2+, Fe2+, Cu2+, and Al3+, has been shown to increase cell death that is characteristic of neurodegenerative disorders such as AD, PD, Wilson’s disease and Menkes disease. These metals are important in numerous biological processes in the brain and their homeostasis is regulated through multiple mechanisms of transport, storage, and secretion. The vertebrate divalent metal transporter-1 (DMT-1) has been implicated in transport and homeostasis of these divalent cations. In these studies I utilize Caenorhabditis elegans (C. elegans) to show that long term exposure to Mn2+ decreases animal viability in a dose-dependent manner, and I demonstrate that C. elegans homologues to DMT-1, SMF-1, SMF-2, and SMF-3, play specific roles in divalent metal ion-induced DA neurodegeneration. I show that SMF-1 contributes to Fe2+-induced DA neuron degeneration, SMF-3 contributes to Al3+-induced DA neuron degeneration, and both SMF-2 and DAT-1 contribute to Cu2+-induced DA neuron cell death. These studies utilize C. elegans as a powerful model to characterize molecules and pathways involved in metal toxicity and metal-induced DA neuron degeneration.

Indiana University-Purdue University Indianapolis (IUPUI) / Signal Transducers and Activators of Transcription 3 (STAT3), a transcription factor expressed in many cell types, including osteoblasts and osteoclasts, is emerging as a key regulator of bone mass and strength. STAT3 mutations cause a rare human immunodeficiency disease characterized by extremely elevated levels of IgE in serum that have associated craniofacial and skeletal features, such as reduced bone mineral density and recurrent pathological fractures. Our microarray data and immunohistochemical staining using a normal rat model have shown that STAT3 mRNA and protein levels markedly increase in response to mechanical loading. In addition, as indicated by STAT3 phosphorylation in MC3T3-E1 osteoblastic cells, STAT3 activity significantly increases in response to 30 to 90 minutes fluid shear stress. In order to further study the role that STAT3 plays in bone responsiveness to loading, tissue-selective STAT3 knockout (KO) mice, in which inactivation of STAT3 occurs in osteoblasts, were generated by breeding the transgenic mice in which Cre recombinase cDNA was cloned downstream of a 3.6 or 2.3 kb fragment of the rat Col1a1 promoter (Col3.6-Cre and Col2.3-Cre, respectively) with a strain of floxed mice in which the two loxP sites flank exons 18-20 of the STAT3 gene were used. Mice engineered with bone selective inactivation of STAT3 in osteoblasts exhibited significantly lower bone mineral density (7-12%, p<0.05) and reduced ultimate force (21-34%, p<0.01) compared to their age-matched littermate controls. The right ulnae of 16-week-old bone specific STAT3 KO mice and the age-matched control mice were loaded with peak forces of 2.5 N and 2.75 N for female and male mice, respectively, at 2 Hz, 120 cycles/day for 3 consecutive days. Mice with inactivation of STAT3 specific in bone were significantly less responsive to mechanical loading than the control mice as indicated by decreased relative mineralizing surface (rMS/BS, 47-59%, p<0.05) and relative bone formation rate (rBFR/BS, 64-75%, p<0.001). Bone responsiveness was equally decreased in mice in which STAT3 is inactivated either in early osteoblasts (Col3.6-Cre) or in mature osteoblasts (Col2.3-Cre). Accumulating evidence indicates that bone metabolism is significantly affected by activities in mitochondria. For instance, although STAT3 is reported to be involved in bone formation and resorption through regulation of nuclear genes, inactivation of STAT3 is shown to disrupt mitochondrial activities and result in an increased level of reactive oxygen species (ROS). Inactivation of STAT3 suppressed load-driven mitochondrial activity, which led to an elevated level of ROS in cultured primary osteoblasts. Oxidative stress induced by administration of buthionine sulfoximine (BSO) significantly inhibits load-induced bone formation in wild type mice. Taken together, the results support the notion that the loss-of-function mutation of STAT3 in osteoblasts and osteocytes diminishes load-driven bone formation and impairs the regulation of oxidative stress in mitochondria.