6 results on '"Nathan N. Alder"'
Search Results
2. Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases
- Author
-
Ashley L. Reed, Wayne Mitchell, Andrei T. Alexandrescu, and Nathan N. Alder
- Subjects
mitochondria ,amyloids ,neurodegeneration ,protein import ,cryptic targeting ,targeting signals ,Physiology ,QP1-981 - Abstract
Most mitochondrial proteins are targeted to the organelle by N-terminal mitochondrial targeting sequences (MTSs, or “presequences”) that are recognized by the import machinery and subsequently cleaved to yield the mature protein. MTSs do not have conserved amino acid compositions, but share common physicochemical properties, including the ability to form amphipathic α-helical structures enriched with basic and hydrophobic residues on alternating faces. The lack of strict sequence conservation implies that some polypeptides can be mistargeted to mitochondria, especially under cellular stress. The pathogenic accumulation of proteins within mitochondria is implicated in many aging-related neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Mechanistically, these diseases may originate in part from mitochondrial interactions with amyloid-β precursor protein (APP) or its cleavage product amyloid-β (Aβ), α-synuclein (α-syn), and mutant forms of huntingtin (mHtt), respectively, that are mediated in part through their associations with the mitochondrial protein import machinery. Emerging evidence suggests that these amyloidogenic proteins may present cryptic targeting signals that act as MTS mimetics and can be recognized by mitochondrial import receptors and transported into different mitochondrial compartments. Accumulation of these mistargeted proteins could overwhelm the import machinery and its associated quality control mechanisms, thereby contributing to neurological disease progression. Alternatively, the uptake of amyloidogenic proteins into mitochondria may be part of a protein quality control mechanism for clearance of cytotoxic proteins. Here we review the pathomechanisms of these diseases as they relate to mitochondrial protein import and effects on mitochondrial function, what features of APP/Aβ, α-syn and mHtt make them suitable substrates for the import machinery, and how this information can be leveraged for the development of therapeutic interventions.
- Published
- 2023
- Full Text
- View/download PDF
3. Phosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc 1 complex function
- Author
-
Elizabeth Calzada, Erica Avery, Pingdewinde N. Sam, Arnab Modak, Chunyan Wang, J. Michael McCaffery, Xianlin Han, Nathan N. Alder, and Steven M. Claypool
- Subjects
Science - Abstract
Phosphatidylethanolamine (PE) is synthesized by four separate pathways, although surprisingly, perturbing mitochondrial PE synthesis compromises mitochondrial function. Here, the authors show that mitochondrial PE synthesis is required for Complex III function and challenge PE trafficking dogma.
- Published
- 2019
- Full Text
- View/download PDF
4. Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds
- Author
-
Wayne Mitchell, Jeffrey D Tamucci, Emery L Ng, Shaoyi Liu, Alexander V Birk, Hazel H Szeto, Eric R May, Andrei T Alexandrescu, and Nathan N Alder
- Subjects
mitochondria ,peptide therapeutics ,membrane interactions ,NMR structure ,structure-activity relationship ,cardiolipin ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register. We present the first structural models for this class of compounds, obtained with Nuclear Magnetic Resonance (NMR) and molecular dynamics approaches, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays. All four peptides were pharmacologically active in serum withdrawal cell stress models yet showed significant differences in their abilities to restore mitochondrial membrane potential, preserve ATP content, and promote cell survival. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register influence the activity of these mitochondria-targeted peptides, helping provide a framework for the rational design of next-generation therapeutics with enhanced potency.
- Published
- 2022
- Full Text
- View/download PDF
5. Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte
- Author
-
Huiliang Zhang, Nathan N Alder, Wang Wang, Hazel Szeto, David J Marcinek, and Peter S Rabinovitch
- Subjects
aging ,mitochondria ,SS-31 ,proton leak ,cardiomyocyte ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. Age-related heart impairment is lacking a clinically effective treatment. Using the model of naturally aging mice and rats, we show direct evidence of increased proton leak in the aged heart mitochondria. Moreover, our data suggested ANT1 as the most likely site of mediating increased mitochondrial proton permeability in old cardiomyocytes. Most importantly, the tetra-peptide SS-31 prevents age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore opening, rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome, and leads to substantial reversal of diastolic dysfunction. Our results uncover the excessive proton leak as a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 can reverse this clinically important complication of cardiac aging.
- Published
- 2020
- Full Text
- View/download PDF
6. The cell-free integration of a polytopic mitochondrial membrane protein into liposomes occurs cotranslationally and in a lipid-dependent manner.
- Author
-
Ashley R Long, Catherine C O'Brien, and Nathan N Alder
- Subjects
Medicine ,Science - Abstract
The ADP/ATP Carrier (AAC) is the most abundant transporter of the mitochondrial inner membrane. The central role that this transporter plays in cellular energy production highlights the importance of understanding its structure, function, and the basis of its pathologies. As a means of preparing proteoliposomes for the study of membrane proteins, several groups have explored the use of cell-free translation systems to facilitate membrane protein integration directly into preformed unilamellar vesicles without the use of surfactants. Using AAC as a model, we report for the first time the detergent-free reconstitution of a mitochondrial inner membrane protein into liposomes using a wheat germ-based in vitro translation system. Using a host of independent approaches, we demonstrate the efficient integration of AAC into vesicles with an inner membrane-mimetic lipid composition and, more importantly, that the integrated AAC is functionally active in transport. By adding liposomes at different stages of the translation reaction, we show that this direct integration is obligatorily cotranslational, and by synthesizing stable ribosome-bound nascent chain intermediates, we show that the nascent AAC polypeptide interacts with lipid vesicles while ribosome-bound. Finally, we show that the presence of the phospholipid cardiolipin in the liposomes specifically enhances AAC translation rate as well as the efficiency of vesicle association and integration. In light of these results, the possible mechanisms of liposome-assisted membrane protein integration during cell-free translation are discussed with respect to the mode of integration and the role of specific lipids.
- Published
- 2012
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.