Project Details
Abstract
Mitochondria, in addition to provide energy for cell, potentially arbitrate apoptosis.
Upon mitochondrial stresses of elevated mitochondrial reactive oxygen species
(mROS) and mitochondrial Ca2+ (mCa2+) mitochondrial membrane permeability
increase to initiate lethal proteins release from the mitochondria for cultivating final
apoptosis. It has been shown that an unstable or a damaged mitochondrial respiratory
chain (RC) augments significantly mitochondrial stress. Using
osteosarcoma-originated cytoplasmic hybridization (cybrids) cells, we have
demonstrated a common deletion of 4977bp mitochondrial DNA (mtDNA) associated
RC defects on complex I, IV and V dose-dependently augments mitochondrial
dysfunction for an enhanced apoptosis. To further narrow down how defects in single
RC complex involve in neurodegeneration and aging, current study focuses solely on
defected mitochondrial complex I (the NADH-ubiquinone oxidoreductase)-induced
alteration of mitochondrial and cellular stresses in astrocytes.
The complex I serves as a 'gateway' for electrons transferred from NADH to
molecular oxygen through the RC. Defects of this complex inhibits directly electrons
transfer on the RC for a reduced energy production and is clinically associated with
mitochondrial diseases, neurodegeneration, and aging including Parkinsonism.
Astrocyte, the most abundant cell type in the CNS, is closely involved not only in
neuronal activities but also critical in pathological neurodegeneration and aging.
Whether and how complex I defects influences mitochondrial and cellular stresses for
astrocytic apoptosis and hence neuronal death, however, is still not clear. The current
grant, thus, is proposed to mechanistically visualize how complex I defects alter
mitochondrial apoptotic stresses of ROS formation, Ca2+ dysregulation. In particular,
how each factor acts alone and/or synergistically with each other to augment
mitochondrial membrane permeability transition for an enhanced apoptosis in
astrocyte will be precisely investigated. A rotenone-induced complex I defects of
astrocytes have been established as a model and will be compared with its control
(without rotenone treatment) and mtDNA less astrocytes (harboring no mtDNA and
hence containing complex I, III, IV and V defects). In addition, two established
cybrids containing mtDNA 4977bp deletion, mtDNA T8993G (complex V defects),
mutant mtDNA encoded ND5 or ND6 subunit of complex I will also be used for
comparison. Time-lapsed fluorescence digital imaging of live mitochondria in single
intact astrocytes will be performed by the application of mitochondrial specific
2
fluorescent probes or proteins coupled with two-or-multiphoton imaging microscopy.
The information released from this study will delineate not only the pathological
mechanisms for complex I defects-induced mitochondrial stresses in astrocytes but
also will contribute significantly to the future therapeutic prevention and treatment of
complex I defects-associated neurodegeneration and aging.
Project IDs
Project ID:PC9902-1686
External Project ID:NSC98-2320-B182-005-MY3
External Project ID:NSC98-2320-B182-005-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/10 → 31/07/11 |
Keywords
- Serratia marcescens
- multicellular behaviou
- swarming
- biofilm
- environmental factors
- quorum sensing
- two component signal transduction system
- pathogenesis
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