A5033955219- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Cellular transport and secretion
- Metabolism and Genetic Disorders
- Photosynthetic Processes and Mechanisms
- Endoplasmic Reticulum Stress and Disease
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Cancer, Hypoxia, and Metabolism
- Erythrocyte Function and Pathophysiology
- Glycosylation and Glycoproteins Research
- Microtubule and mitosis dynamics
- Lipid Membrane Structure and Behavior
- Autophagy in Disease and Therapy
- RNA Research and Splicing
- Glioma Diagnosis and Treatment
- Bacterial Genetics and Biotechnology
- Genetic and Kidney Cyst Diseases
- Lysosomal Storage Disorders Research
- Reproductive Biology and Fertility
- Cholesterol and Lipid Metabolism
- Ubiquitin and proteasome pathways
- Galectins and Cancer Biology
- Advanced Electron Microscopy Techniques and Applications
- Endometriosis Research and Treatment
Case Western Reserve University
2016-2025
University School
2014-2025
Brigham and Women's Hospital
2023
Broad Institute
2023
Harvard University
2023
Cornell University
2021
Case Comprehensive Cancer Center
2021
CSL (United States)
2021
Parsons (United States)
2015
National Institute of Diabetes and Digestive and Kidney Diseases
2005-2011
Dynamin-related proteins (DRPs) are large self-assembling GTPases whose common function is to regulate membrane dynamics in a variety of cellular processes. Dnm1, which yeast DRP (Drp1/Dlp1 humans), required for mitochondrial division, but its mechanism unknown. We provide evidence that Dnm1 likely functions through self-assembly drive the constriction event associated with division. Two regulatory features were also identified. proceeded rate-limiting nucleation step, and nucleotide...
The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications on tumor biology are poorly understood. Here we show that is a prevalent phenomenon glioblastoma (GBM), most frequent and malignant primary brain tumor. We identified horizontal from astrocytes as mechanism enhances tumorigenesis GBM. This dependent network-forming intercellular connections GBM cells astrocytes, which facilitated...
The GTPase dynamin catalyzes membrane fission by forming a collar around the necks of clathrin-coated pits, but specific structural interactions and conformational changes that drive this process remain mystery. We present GMPPCP-bound structures truncated human 1 helical polymer at 12.2 Å fusion protein, GG, linking 1's catalytic G domain to its effector (GED) 2.2 Å. reveal position connectivity fragments in assembled structure, showing dimers only form between tetramers sequential rungs...
Sterols are transferred between cellular membranes by vesicular and poorly understood nonvesicular pathways. Oxysterol-binding protein–related proteins (ORPs) have been implicated in sterol sensing transport. In this study, we show that yeast ORPs use a novel mechanism allows regulated transfer closely apposed membranes, such as organelle contact sites. We find the core lipid-binding domain found all can simultaneously bind two membranes. Using Osh4p/Kes1p representative ORP, at least...
The GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial division, but the mechanisms remain poorly understood. Much of what is attributed to Drp1’s mechanism action in membrane fission parallels that prototypical dynamin endocytic vesicle scission. Unlike case for dynamin, however, no lipid target Drp1 activation at mitochondria has been identified. In addition, oligomerization properties have not well established. We show mitochondria-specific cardiolipin a potent stimulator...
Cardiolipin (CL) is an atypical, dimeric phospholipid essential for mitochondrial dynamics in eukaryotic cells. Dynamin-related protein 1 (Drp1), a cytosolic member of the dynamin superfamily large GTPases, interacts with CL and functions to sustain balance division fusion by catalyzing fission. Although recent studies have indicated role stimulating Drp1 self-assembly GTPase activity at membrane surface, mechanism which fission, if all, remains unclear. Here, using variety fluorescence...
Abstract Dynamins are mechano-chemical GTPases involved in the remodeling of cellular membranes. In this study, we have investigated mechanism dynamin-related protein 1 (Drp1), a key mediator mitochondrial fission. To date, it is unclear how Drp1 assembles on outer membrane response to different lipid signals induce Here, present cryo-EM structures helices nanotubes with distinct compositions mimic interactions fission machinery. These polymers assemble exclusively through stalk and G-domain...
Abstract Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at surface mitochondria. As such, Drp1 essential for inducing mitochondrial division in mammalian cells, homologous proteins are found all eukaryotes. member dynamin superfamily (DSPs), controlled self-assembly into large helical polymers stimulates its GTPase activity promote membrane...
ABSTRACT Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present encephalopathy due to defective mitochondrial peroxisomal fission (EMPF1) – a devastating neurodevelopmental disease no effective treatment. To interrogate mechanisms which DRP1 cause cellular dysfunction, we used human-derived fibroblasts from...
The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at extreme Drp1 C-terminus, named CT-SLiM, constitutes critical allosteric site controls structure function in vitro vivo. Extension of CT-SLiM by non-native residues, or its interaction with partner GIPC-1, constrains subunit conformational dynamics,...
To examine the cause of altered follicular fluid steroid levels and lower in vitro fertilization rate observed infertile women with minor endometriosis, we have compared production estradiol (aromatase activity) progesterone freshly isolated granulosa cells (3h. incubation) from such a control group tubal or unexplained infertility, having IVF during unstimulated gonadotropin-stimulated cycles. As previously observed, mature oocytes endometriosis had reduced cleavage cycles (19/37[51%] vs....
Green fluorescent protein (GFP)-tagging is the prevalent strategy to monitor dynamics in living cells. However, consequences of appending bulky GFP moiety interest are rarely investigated. Here, using a powerful combination quantitative fluorescence spectroscopic and imaging techniques, we have examined oligomerization GFP-tagged mitochondrial fission GTPase dynamin-related 1 (Drp1) both vitro vivo. We find that Drp1 exhibits impaired equilibria solution corresponds greatly diminished...
Abstract O -GlcNAcylation is a prevalent form of glycosylation that regulates proteins within the cytosol, nucleus, and mitochondria. The -GlcNAc modification can affect protein cellular localization, function, signaling interactions. specific impact on mitochondrial morphology function has been elusive. In this manuscript, role fission, oxidative phosphorylation (Oxphos), activity electron transport chain (ETC) complexes were evaluated. environment with hyper due to deletion -GlcNAcase...
Abstract The self-assembling, mechanoenzymatic dynamin superfamily GTPase, dynamin-related protein 1 (Drp1), catalyzes mitochondrial and peroxisomal fission. Distinct intrinsically disordered regions (IDRs) in Drp1 substitute for the canonical pleckstrin homology (PH) domain proline-rich (PRD) of prototypical dynamin, which cooperatively regulate endocytic vesicle scission. Whether IDRs function analogously to corresponding domains however remains unknown. We show that an IDR unique GTPase...
Nocturnal hypoxaemia, which is common in chronic obstructive pulmonary disease (COPD) patients, associated with skeletal muscle loss or sarcopenia, contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of occurs through sleep followed by normoxia during day, contrast recurrent brief hypoxic episodes apnoea (OSA). Adaptive cellular responses PIH are not known. Responses induced three cycles 8 h 16 were compared...
Abstract Patient mutations have been identified throughout dynamin-related protein 1 (Drp1), the key mediator of mitochondrial fission. These changes generally impact young children and often result in severe neurological defects and, some instances, death. Until now, underlying functional defect leading to patient phenotypes has largely speculative. We therefore analyzed six disease-associated GTPase middle domains (MD) Drp1. The MD plays a role Drp1 oligomerization, three this region were...