Satish Srinivasan

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The environmental toxin 2,3,7,8-tetrachlorodibenzodioxin (TCDD) is a known human carcinogen; however, its precise mechanism of action remains unclear. Here we show that TCDD induces mitochondrial dysfunction, stress signaling, and tumor invasion by a mechanism similar to that described for mtDNA-depleted cells. Treatment of C2C12 cells with TCDD disrupted(More)
Cytochrome c oxidase (CcO) is the terminal oxidase of the mitochondrial electron transport chain. This bigenomic enzyme in mammals contains 13 subunits of which the 3 catalytic subunits are encoded by the mitochondrial genes. The remaining 10 subunits with suspected roles in the regulation, and/or assembly, are coded by the nuclear genome. The enzyme(More)
We have investigated the effects of hypoxia and myocardial ischemia/reperfusion on the structure and function of cytochrome c oxidase (CcO). Hypoxia (0.1% O(2) for 10 h) and cAMP-mediated inhibition of CcO activity were accompanied by hyperphosphorylation of subunits I, IVi1, and Vb and markedly increased reactive O(2) species production by the enzyme(More)
CcO (cytochrome c oxidase) is a multisubunit bigenomic protein complex which catalyses the last step of the mitochondrial electron transport chain. The nuclear-encoded subunits are thought to have roles either in regulation or in the structural stability of the enzyme. Subunit Vb is a peripheral nuclear-encoded subunit of mammalian CcO that is dramatically(More)
How receptors catalyze exchange of GTP for GDP bound to the Galpha subunit of trimeric G proteins is not known. One proposal is that the receptor uses the G protein's betagamma heterodimer as a lever, tilting it to pull open the guanine nucleotide binding pocket of Galpha. To test this possibility, we designed a mutant Galpha that would bind to betagamma in(More)
Metastatic breast tumors undergo epithelial-to-mesenchymal transition (EMT), which renders them resistant to therapies targeted to the primary cancers. The mechanistic link between mtDNA (mitochondrial DNA) reduction, often seen in breast cancer patients, and EMT is unknown. We demonstrate that reducing mtDNA content in human mammary epithelial cells(More)
Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset(More)
Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a(More)
Previously we showed that hypoxia-induced mitochondrial respiratory stress in RAW 264.7 macrophages and other cells caused activation of retrograde signaling (also known as mitochondrial respiratory stress signaling) and the appearance of tartrate-resistant acid phosphatase (TRAP)-positive cells. In the present study, we used N-acetyl cysteine and ascorbate(More)
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an(More)