A5091401780- Mitochondrial Function and Pathology
- Heat shock proteins research
- ATP Synthase and ATPases Research
- Endoplasmic Reticulum Stress and Disease
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- thermodynamics and calorimetric analyses
- Redox biology and oxidative stress
- Metabolism and Genetic Disorders
- Alzheimer's disease research and treatments
- Photosynthetic Processes and Mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Peptidase Inhibition and Analysis
- Fungal and yeast genetics research
- Metabolomics and Mass Spectrometry Studies
- Prion Diseases and Protein Misfolding
- Microbial Metabolic Engineering and Bioproduction
- Metal-Catalyzed Oxygenation Mechanisms
- RNA Research and Splicing
- Advanced Glycation End Products research
- Coenzyme Q10 studies and effects
- Biochemical and Structural Characterization
- Genetic Neurodegenerative Diseases
- Signaling Pathways in Disease
University of Bonn
2014-2024
Columbia University Irving Medical Center
2013
University of Freiburg
2000-2009
Osnabrück University
2006
Centre National de la Recherche Scientifique
2006
La Trobe University
2006
Centre de Génétique Moléculaire
2006
University of Oregon
1998
University of Geneva
1994
University of Wisconsin–Madison
1993-1994
Familial Parkinson disease is associated with mutations in α-synuclein (α-syn), a presynaptic protein that has been localized not only to the cytosol, but also mitochondria. We report here wild-type α-syn from cell lines, and brain tissue humans mice, present mitochondria rather mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), structurally functionally distinct subdomain of ER. Remarkably, we found pathogenic point human result its reduced association MAM, coincident lower...
The role of mitochondrial 70-kD heat shock protein (mt-hsp70) in translocation across both the outer and inner membranes was studied using two temperature-sensitive yeast mutants. degree polypeptide into matrix mutant mitochondria analyzed a matrix-targeted preprotein that cleaved twice by processing peptidase. A short amino-terminal segment (40-60 amino acids) driven membrane potential, independent hsp70 function, allowing single cleavage presequence. Artificial unfolding allowed complete...
Transport of preproteins into the mitochondrial matrix is mediated by presequence translocase–associated motor (PAM). Three essential subunits are known: Hsp70 (mtHsp70); peripheral membrane protein Tim44; and nucleotide exchange factor Mge1. We have identified fourth subunit PAM, an inner 18 kD with a J-domain that stimulates ATPase activity mtHsp70. The novel J-protein (encoded PAM18/YLR008c/TIM14) required for interaction mtHsp70 Tim44 translocation matrix. conclude reaction cycle PAM...
Transport of metabolites across the mitochondrial inner membrane is highly selective, thereby maintaining electrochemical proton gradient that functions as main driving force for cellular adenosine triphosphate synthesis. Mitochondria import many preproteins via presequence translocase membrane. However, reconstituted Tim23 protein constitutes a pore remaining mainly in its open form, state would be deleterious organello. We found intermembrane space domain Tim50 induced channel to close....
Proteins in a natural environment are constantly challenged by stress conditions, causing their destabilization, unfolding, and, ultimately, aggregation. Protein aggregation has been associated with wide variety of pathological especially neurodegenerative disorders, stressing the importance adequate cellular protein quality control measures to counteract aggregate formation. To secure homeostasis, mitochondria contain an elaborate system, consisting chaperones and ATP-dependent proteases....
Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidence has shown intraneuronal accumulation and interference mitochondrial functions. Nevertheless, relevance intracellular pathophysiology AD is controversial. Here we found that two major species peptides, particular Aβ42, exhibited strong inhibitory effect on preprotein import reactions essential for biogenesis. However, interacted...
To test the hypothesis that 70-kD mitochondrial heat shock protein (mt-hsp70) has a dual role in membrane translocation of preproteins we screened an attempt to find examples which required either only unfoldase or translocase function mt-hsp70. We found series fusion proteins containing amino-terminal portions intermembrane space cytochrome b2 (cyt. b2) fused dihydrofolate reductase (DHFR) were differentially imported into mitochondria mutant hsp70s. A between 167 residues precursor cyt....
Transport of preproteins into the mitochondrial matrix requires presequence translocase inner membrane (TIM23 complex) and translocase-associated motor (PAM). The consists five essential subunits, heat shock protein 70 (mtHsp70) four cochaperones, nucleotide exchange-factor Mge1, fulcrum Tim44, J-protein Pam18, Pam16. Pam16 forms a complex with Pam18 displays similarity to J-proteins but lacks canonical tripeptide motif His-Pro-Asp (HPD). We report that does not function as typical J-domain...
Abstract Mitochondria contribute significantly to the cellular production of ROS. The deleterious effects increased ROS levels have been implicated in a wide variety pathological reactions. Apart from direct detoxification molecules, protein quality control mechanisms are thought protect functions presence elevated levels. reactivities molecular chaperones and proteases remove damaged polypeptides, maintaining enzyme activities, thereby contributing survival both under normal stress...
The Parkinson disease-associated kinase Pink1 is targeted to mitochondria where it thought regulate mitochondrial quality control by promoting the selective autophagic removal of dysfunctional mitochondria. Nevertheless, targeting mode and its submitochondrial localization are still not conclusively resolved. aim this study was dissect import pathway use a highly sensitive in vitro assay. Mutational analysis sequence revealed that N terminus acts as genuine matrix mediates initial membrane...
The essential yeast gene MPI1 encodes a mitochondrial membrane protein that is possibly involved in import into the organelle (A. C. Maarse, J. Blom, L. A. Grivell, and M. Meijer, EMBO 11:3619-3628, 1992). For this report, we determined submitochondrial location of product investigated whether it plays direct role translocation preproteins. By fractionation mitochondria, mature 44 kDa was localized to inner therefore termed MIM44. Import precursor MIM44 required potential across proteolytic...
The dynamic vesicle transport processes at the late-Golgi compartment of Saccharomyces cerevisiae (TGN) require dedicated mechanisms for correct localization resident membrane proteins. In this study, we report identification a new gene, GRD19, involved in model protein A-ALP (consisting cytosolic domain dipeptidyl aminopeptidase A [DPAP A] fused to transmembrane and lumenal domains alkaline phosphatase [ALP]), which localizes yeast TGN. grd19 null mutation causes rapid mislocalization...
ATP-dependent oligomeric proteases are major components of cellular protein quality control systems. To investigate the role proteolytic processes in maintenance mitochondrial functions, we analyzed dynamic behavior proteome Saccharomyces cerevisiae by two-dimensional (2D) polyacrylamide gel electrophoresis. By a characterization influence temperature on turnover isolated mitochondria, were able to define four groups proteins showing differential susceptibility proteolysis. The Pim1/LON has...