Browsing by Subject "Mitochondrial morphology"

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    CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer’s Disease
    (MDPI, 2023-04-29) Brustovetsky, Tatiana; Khanna, Rajesh; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of Medicine
    Mitochondrial bioenergetics and dynamics (alterations in morphology and motility of mitochondria) play critical roles in neuronal reactions to varying energy requirements in health and disease. In Alzheimer’s disease (AD), mitochondria undergo excessive fission and become less motile. The mechanisms leading to these alterations are not completely clear. Here, we show that collapsin response mediator protein 2 (CRMP2) is hyperphosphorylated in AD and that is accompanied by a decreased interaction of CRMP2 with Drp1, Miro 2, and Mitofusin 2, which are proteins involved in regulating mitochondrial morphology and motility. CRMP2 was hyperphosphorylated in postmortem brain tissues of AD patients, in brain lysates, and in cultured cortical neurons from the double transgenic APP/PS1 mice, an AD mouse model. CRMP2 hyperphosphorylation and dissociation from its binding partners correlated with increased Drp1 recruitment to mitochondria, augmented mitochondrial fragmentation, and reduced mitochondrial motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Ser 522 and Thr 509/514, and restored CRMP2′s interaction with Miro 2, Drp1, and Mitofusin 2. This was paralleled by decreased Drp1 recruitment to mitochondria, diminished mitochondrial fragmentation, and improved motility of the organelles. Additionally, (S)-LCM-protected cultured cortical AD neurons from cell death. Thus, our data suggest that CRMP2, in a phosphorylation-dependent manner, participates in the regulation of mitochondrial morphology and motility, and modulates neuronal survival in AD.
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    Mitochondrial behaviour throughout the lytic cycle of Toxoplasma gondii
    (SpringerNature, 2017-02-16) Ovciarikova, Jana; Lemgruber, Leandro; Stilger, Krista L.; Sullivan, William J., Jr.; Sheiner, Lilach; Department of Pharmacology and Toxicology, IU School of Medicine
    Mitochondria distribution in cells controls cellular physiology in health and disease. Here we describe the mitochondrial morphology and positioning found in the different stages of the lytic cycle of the eukaryotic single-cell parasite Toxoplasma gondii. The lytic cycle, driven by the tachyzoite life stage, is responsible for acute toxoplasmosis. It is known that whilst inside a host cell the tachyzoite maintains its single mitochondrion at its periphery. We found that upon parasite transition from the host cell to the extracellular matrix, mitochondrion morphology radically changes, resulting in a reduction in peripheral proximity. This change is reversible upon return to the host, indicating that an active mechanism maintains the peripheral positioning found in the intracellular stages. Comparison between the two states by electron microscopy identified regions of coupling between the mitochondrion outer membrane and the parasite pellicle, whose features suggest the presence of membrane contact sites, and whose abundance changes during the transition between intra- and extra-cellular states. These novel observations pave the way for future research to identify molecular mechanisms involved in mitochondrial distribution in Toxoplasma and the consequences of these mitochondrion changes on parasite physiology.