Investigations into the contributions of mitochondrial dynamics and function to platelet ageing and reactivity
Abstract
Platelets are essential for the physiological process of haemostasis, but also drive
pathological thrombosis. Platelet lifespan is a tightly controlled process through
which platelets exist for approximately 10 days within the circulation of healthy
individuals. However, in a number of disease states this process is dysregulated
leading to an accelerated platelet turnover. Indeed, there are a number of reports
suggesting that newly formed platelets are hyper-reactive and their presence has
been associated with a higher risk of thrombosis. Whilst there are these indications
of hyper-reactivity in young platelets, there are few systematic studies. Here I have
used proteomics coupled with functional studies and immunofluorescence to show
that there is a progressive decline in mitochondrial and cytoskeletal proteins as
platelets age and an increase in apoptotic pathways. Given the apparent importance
of mitochondria in supporting the predetermined platelet lifespan, it raised the
question as to whether mitochondria are important for other platelet functional
processes. Therefore, I sought to elucidate the impact of platelet activation on
mitochondrial function and dynamics. Physiological stimulation causes an increase in
mitochondrial respiration, consistent with an increase in energy demand.
Interestingly, P2Y12 receptor inhibition causes a reduction in basal oxygen
consumption, suggesting a dysregulation in mitochondrial function. Furthermore,
this work highlights a role for mitochondria beyond energy production, with
indications that stimulation causes platelets to package and release their
mitochondria into microvesicles. Interestingly, these mitochondria-containing
microvesicles have high P-selectin expression suggesting they may be more likely to
interact with neutrophils than the rest of the microvesicle population. Indeed,
incubation of neutrophils with mitochondria-positive microvesicles but not
mitochondria-negative microvesicles causes alterations in the expression of surface
markers; CD11b, CD66b and CXCR2, indicative of neutrophil activation potentially as
a result of phagocytosis. This work highlights an important role of mitochondria in
both platelet ageing and activation.
Authors
Allan, Harriet ElizabethCollections
- Theses [4099]