Defects in the capability of the mitochondrial electron transport chain to participate in oxidative phosphorylation and in mitochondrial fission-fusion dynamics are hallmark characteristics of neurodegenerative diseases, including Alzheimer’s Disease and Lewy Body Dementia. This mitochondrial dysfunction is bidirectionally influenced by chronic pro-inflammatory microglial activation and is believed to be a key contributor to the onset and progression of neurodegenerative conditions. This dissertation tested two hypotheses related to immunometabolism in neurodegeneration. First, we tested if genetic ablation of the endolysosomal cation channel TPC1 – mimicking loss of expression seen in the microglia of dementia patients – would result in mitochondrial bioenergetic dysfunction. We found that commercially available TPCN1 knockout HAP1 cells exhibit deficits in mitochondrial oxygen consumption and electron transport chain protein subunit expression. Despite prior implication of TPC1 in mitophagy, these protein-level decreases were not attributable to autophagy or proteasomal activity, conventional mechanisms for post-translational regulation of mitochondrial homeostasis. Furthermore, we were unable to rescue these deficits by TPC1 protein overexpression and identified many de novo mutations that might alternatively contribute to the phenotype, leaving the requirement of TPC1 for mitochondrial homeostasis unresolved. These findings highlight the need for increased rigor in haploid model knockout studies. Second, we tested if inhibiting mitochondrial fission is required for suppression of nitric oxide release from pro-inflammatory microglia by the DRP1 inhibitor mdivi-1. We found mdivi-1 suppressed NO release but failed to block acquisition of rounded mitochondrial morphology following stimulation of HAPI microglial cells with lipopolysaccharide and interferon-gamma. We also found that a structurally distant, more potent DRP1 inhibitor, Drpitor1a, failed to recapitulate protective effects of mdivi-1, while mdivi-1’s protective effects on NO secretion were mimicked by the FGFR inhibitor infigratinib. These results provide indirect support for an alternative mechanism of mdivi-1 protective action. In addition to these hypothesis-driven studies, this dissertation also addresses limitations of existing in vitro model systems for the study of microglial immunometabolism, by recharacterizing HAPI cells as a mouse microglia-like cell line exhibiting suppression of mitochondrial oxygen consumption in response to classical pro-inflammatory stimuli and by conducting the first bioenergetic studies of human monocyte-derived microglia and induced pluripotent stem cell-derived iTF-Microglia.