Hypoxia causes aggregation of serine palmitoyltransferase followed by non-apoptotic death of human lymphocytes.
In the central nervous system chronic hypoxia has been suggested to cause neurodegenerations and protein aggregation, as in Alzheimer's disease. Here we have shown protein aggregation during acute hypoxia in human primary cells. Clinically relevant acute hypoxia (pO(2) = 25 mmHg) was produced by incubation of venous blood in vitro, where 18-hour incubation resulted in raise of pCO(2) to 90 mmHg, accumulation of lactate and acidosis (pH 7.06). In hypoxic samples the number of necrotic, but not apoptotic, white blood cells increased to 9.6%. Viable cells displayed hypoxia-related changes such as a drop of mitochondrial membrane potential and changes in the plasma membrane. These changes coincided with the 2.6-fold increase in immunoreactivity of serine palmitoyltransferase subunit 1 (SPT1), which is the enzyme involved in HSN1-type neurodegeneration. SPT1 immunoreactivity was presented as large cytosolic aggregates, which appeared in viable hypoxic cells and remained in dead cells. SPT-positive aggregates were also found in cell nuclei. This data suggests that SPT1 aggregation preceded cell death in hypoxia and represents the first evidence of acute protein aggregation during hypoxia.
Dedov
Vadim N
VN
Neurobiology Laboratory, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, Australia. vdedov@med.usyd.edu.au
Dedova
Irina V
IV
Nicholson
Garth A
GA
D000199:Actins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials; D009336:Necrosis; D011487:Protein Conformation; D051102:Serine C-Palmitoyltransferase / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors
D000199:Actins; D051102:Serine C-Palmitoyltransferase