Excessive reactive oxygen species induces apoptosis in fibroblasts: role of mitochondrially accumulated hyaluronic acid binding protein 1 (HABP1/p32/gC1qR).
Constitutively expressed HABP1 in normal murine fibroblast cell line induces growth perturbation, morphological abnormalities along with initiation of apoptosis. Here, we demonstrate that though HABP1 accumulation started in mitochondria from 48 hr of growth, induction of apoptosis with the release of cytochrome c and apoptosome complex formation occurred only after 60 hr. This mitochondrial dysfunction was due to gradual increase in ROS generation in HABP1 overexpressing cells. Along with ROS generation, increased Ca 2+ influx in mitochondria leading to drop in membrane potential was evident. Interestingly, upon expression of HABP1, the respiratory chain complex I was shown to be significantly inhibited. Electronmicrograph confirmed defective mitochondrial ultrastructure. The reduction in oxidant generation and drop in apoptotic cell population accomplished by disruption of HABP1 expression, corroborating the fact that excess ROS generation in HABP1 overexpressing cells leading to apoptosis was due to mitochondrial HABP1 accumulation.
Chowdhury
Anindya Roy
AR
Biochemistry Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
Ghosh
Ilora
I
Datta
Kasturi
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053478:Apoptosomes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
D053478:Apoptosomes; C490193:C1qbp protein, mouse; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D042967:Electron Transport Complex I