Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development.
Thyroid hormone (TH) deficiency leads to extensive apoptosis during cerebellar development, but the mechanism still remains unclear. Different signals also converge on mitochondria during apoptosis to induce the release of apoptogenic proteins that activate proteolytic cascade through specific enzymes called caspases. Here we studied the effect of hypothyroidism on alterations in mitochondrial structure and translocation of apoptogenic molecules during rat cerebellar development. Structural analysis of mitochondria was studied by electron microscopy. The translocation of apoptogenic molecules was analyzed by Western blotting. TH deficiency led to vacuolization, enlargement and decrease in the number of cristae. The majority of the proapoptotic molecule, Bax, was localized in mitochondria under hypothyroid conditions whereas a limited presence of Bax was detected in the euthyroid state. Translocation of cytochrome c, apoptosis-inducing factor (AIF) and second mitochondrial-derived activator of caspases (SMAC) from mitochondria to cytosol was detected primarily in early developmental stages in the hypothyroid condition. These experimental results demonstrate that TH maintains mitochondrial architecture and inhibits the release of apoptogenic molecules to prevent excess apoptosis during cerebellar development.
Singh
R
R
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India.
Upadhyay
Geeta
G
Godbole
M M
MM
D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism / Q000648:ultrastructure*; D003574:Cytochrome c Group / Q000235:genetics; D005420:Flavoproteins / Q000235:genetics; D007037:Hypothyroidism / Q000378:metabolism / Q000473:pathology*; D007093:Imidazoles; D008565:Membrane Proteins / Q000235:genetics; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000235:genetics; D023421:Models, Animal; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D014178:Translocation, Genetic; D051028:bcl-2-Associated X Protein
C107674:2-mercapto-1-methylimidazole; C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C494828:Bax protein, rat; D002352:Carrier Proteins; D003574:Cytochrome c Group; C489013:DIABLO protein, rat; D005420:Flavoproteins; D007093:Imidazoles; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein