A5016601719- Mitochondrial Function and Pathology
- Autophagy in Disease and Therapy
- ATP Synthase and ATPases Research
- Parkinson's Disease Mechanisms and Treatments
- Photosynthetic Processes and Mechanisms
- Protease and Inhibitor Mechanisms
- Metabolism and Genetic Disorders
- Peroxisome Proliferator-Activated Receptors
- Peptidase Inhibition and Analysis
- Genetics, Aging, and Longevity in Model Organisms
- Alzheimer's disease research and treatments
- Sleep and Wakefulness Research
- Cell Adhesion Molecules Research
- Metabolomics and Mass Spectrometry Studies
- Ubiquitin and proteasome pathways
- Studies on Chitinases and Chitosanases
- Computational Drug Discovery Methods
- Biochemical Acid Research Studies
- Heme Oxygenase-1 and Carbon Monoxide
- Enzyme Structure and Function
- Enzyme function and inhibition
- Genetic Neurodegenerative Diseases
- Cannabis and Cannabinoid Research
- Plant and Fungal Interactions Research
- Lysosomal Storage Disorders Research
University of Toronto
2012-2023
Canada Research Chairs
2011-2020
The King's College
2011
Parker Hannifin (United States)
2009
Miele (Germany)
2009
Hospital for Sick Children
2009
SickKids Foundation
2009
MRC Laboratory of Molecular Biology
2003-2006
University of British Columbia
2000-2003
University of Calgary
2002
Tissue degradation by the matrix metalloproteinase gelatinase A is pivotal to inflammation and metastases. Recognizing catalytic importance of substrate-binding exosites outside domain, we screened for extracellular substrates using hemopexin domain as bait in yeast two-hybrid system. Monocyte chemoattractant protein–3 (MCP-3) was identified a physiological substrate A. Cleaved MCP-3 binds CC-chemokine receptors–1, –2, –3, but no longer induces calcium fluxes or promotes chemotaxis, instead...
Reactive oxygen species (ROS) have been implicated as a signal for general autophagy. Both mitochondrial-produced and exogenous ROS induce autophagosome formation. However, it is unclear whether are required the selective autophagic degradation of mitochondria, process called mitophagy. Recent work using carbonyl cyanide m-chlorophenylhydrazone (CCCP), mitochondrial-uncoupling reagent, has shown to CCCP treatment may not be biologically relevant since causes depolarization entire...
Abstract Parasitic nematodes infect one quarter of the world’s population and impact all humans through widespread infection crops livestock. Resistance to current anthelmintics has prompted search for new drugs. Traditional screens that rely on parasitic worms are costly labour intensive target-based approaches have failed yield novel anthelmintics. Here, we present our screen 67,012 compounds identify those kill non-parasitic nematode Caenorhabditis elegans . We then rescreen hits in two...
The selective degradation of mitochondria by the process autophagy, termed mitophagy, is one major mechanisms mitochondrial quality control. best-studied mitophagy pathway mediated PINK1 and PARK2/Parkin. From recent studies it has become clear that ubiquitin-ligation plays a pivotal role most focus been on ubiquitination proteins in mitophagy. Even though reversible process, very little known about deubiquitinating enzymes (DUBs) Here, we report 2 DUBs, USP30 USP35, regulate PARK2-mediated...
Parkinson's disease (PD) is a common neurodegenerative disorder caused by loss of midbrain dopaminergic neurons, the pathogenetic mechanisms which remain unclear. Mitochondrial dysfunction, has long been implicated in sporadic PD, recently highlighted as key pathological cause, particularly with identification mutations PTEN-induced putative kinase (pink1), parkin and htrA2 (also known omi) genes that are linked to PD. Studies Drosophila melanogaster have shown pink1 act genetic pathway...
Molecular genetics has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease by discovery rare, inherited mutations in gene products that associate with mitochondria. Mutations PTEN-induced kinase-1 (PINK1), which encodes a kinase, and PARKIN, encoding an E3 ubiquitin ligase, are most frequent causes recessive disease. Recent functional studies have revealed PINK1 recruits PARKIN mitochondria initiate mitophagy, important autophagic quality control mechanism rids cell...
Abstract The accumulation of damaged mitochondria causes the death dopaminergic neurons. Parkin-mediated mitophagy pathway functions to remove these from cells. Targeting this represents a therapeutic strategy for several neurodegenerative diseases, most notably Parkinson’s disease. We describe discovery pipeline identify small molecules that increase Parkin recruitment and ensuing mitophagy. show ROCK inhibitors promote activity by increasing HK2, positive regulator Parkin, mitochondria....
Phosphatidylethanolamine is proposed to regulate mitochondrial fusion, but its mechanism of action unknown.Decreasing phosphatidylethanolamine reduces the rate lipid mixing and biogenesis Mgm1, a fusion protein.Psd1 regulates protein machineries fusion.Understanding how metabolism dynamics will reveal role in cellular functions such as apoptosis autophagy. Non-bilayer-forming lipids cardiolipin, phosphatidic acid, (PE) are generate negative membrane curvature, promoting fusion. However, by...
Mitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism the pathogenesis various diseases, including Parkinson's disease. The mammalian rhomboid protease, PARL, has been proposed regulator PINK1/PARKIN-mediated mitophagy, which an component MQC. PARL undergoes N-terminal autocatalytic cleavage (β cleavage), required efficient mitophagy. We demonstrate that β responds to stress,...
The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes highly dynamic, changing response to metabolic stress. our recent study identifying mitophagy, observed be localized punctate structures resembling peroxisomes. We report here that USP30, best known as mitophagy regulator, also necessary...
Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes detected removed from the cell is poorly understood. Recent studies suggest that peroxisomal matrix protein import machinery may serve double duty as quality control machinery, where they directly involved in activating Here, we explored whether any factors required to prevent pexophagy, such their loss designates for degradation. Using...
Mitochondrial morphology is regulated by the post-translational modifications of dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein (DRP1). phosphatase phosphoglycerate mutase 5 (PGAM5) emerging as a regulator these modifications; however, its precise role in regulation mitochondrial unknown. We show that PGAM5 interacts with MFN2 DRP1 stress-sensitive manner. regulates phosphorylation consequently protects it from ubiquitination degradation....
Mgm1, the yeast ortholog of mammalian OPA1, is a key component in mitochondrial membrane fusion and required for maintaining dynamics morphology. We showed recently that purified short isoform Mgm1 (s-Mgm1) possesses GTPase activity, self-assembles into low order oligomers, interacts specifically with negatively charged phospholipids (Meglei, G., McQuibban, G. A. (2009) Biochemistry 48, 1774–1784). Here, we demonstrate s-Mgm1 binds to mixture characteristic inner membrane. Binding...
Failures in mitophagy, a process by which damaged mitochondria are cleared, results neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed natural language processing approach to evaluate semantic similarity candidate molecules set well-established enhancers. Top candidates were screened cell-based mitochondrial clearance assay. Probucol, lipid-lowering drug, was validated across several orthogonal...
On the cell surface, 59-kDa membrane type 1-matrix metalloproteinase (MT1-MMP) activates 72-kDa progelatinase A (MMP-2) after binding tissue inhibitor of metalloproteinases (TIMP)-2. 44-kDa remnant MT1-MMP, with an N terminus at Gly<sup>285</sup>, is also present on autolytic shedding catalytic domain from hemopexin carboxyl (C) domain, but its role in gelatinase activation unknown. We investigated intermolecular interactions complex using recombinant proteins, domains, and peptides, yeast...
Mitochondrial dynamics resulting from competing membrane fusion and fission reactions are required for normal cellular function in eukaryotes. Mgm1p, a dynamin-related protein, is key component yeast mitochondrial evolutionarily conserved. Previous studies suggest that Mgm1p mediates inner manner similar to of other dynamin proteins use GTP hydrolysis oligomerization induce structural changes lipid bilayers; however, direct demonstration these activities has yet be presented. Here we show...
Significance A hypothesis for the paradoxical evolution of programmed cell death posits that suicide mechanisms were co-opted from processes originally pro-survival. Here we show meiotically mitochondrial release Endonuclease G (EndoG) homolog Nuc1 occurs during sporulation in budding yeast. While EndoG is implicated animal apoptotic death, find pro-survival, protecting spores detrimental consequences unrestrained viral expression.
Mitochondrial impairment is a hallmark feature of neurodegenerative disorders, such as Parkinson disease, and PRKN/parkin-mediated mitophagy serves to remove unhealthy mitochondria from cells. Notably, probiotics are used alleviate several symptoms disease including impaired locomotion neurodegeneration in preclinical studies constipation clinical trials. There some evidence suggest that can modulate mitochondrial quality control pathways. In this study, we screened 49 probiotic strains...