23 Mitochondrial motility and vascular smooth muscle proliferation

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Mitochondrial function is critical for multiple facets of cellular function including ATP production and calcium handling. Subcellular location of the organelle is important for function. In smooth muscle, mitochondria modulate calcium signals arising from inositol- trisphosphate receptors, even localised calcium puffs, revealing a close physical relationship between the sarcoplasmic reticulum and mitochondria. This seems incompatible with the free movement of mitochondria observed in several cell types. Mitochondrial mobility was imaged in intact cerebral resistance arteries at physiological pressure. Arteries were maintained in organ culture for up to 4 days. Protein expression was measured by western blotting and immunocytochemistry in fixed, pressurised arteries. Proliferation was measured by proliferating cell nuclear antigen (PCNA) staining, thymidine incorporation and fluorescence-activated cell sorting by propidium iodide incorporation. In intact cerebral arteries, individual mitochondria within smooth muscle were largely stationary; however in a small number of cells mitochondria displayed large-scale directed movements. When arteries were maintained in organ culture to promote proliferation, an increased number of cells showing moving mitochondria and an increase in the extent of movement occurred. Expression of the mitochondrial tether mitofusin-2 decreased and PCNA increased. Maintenance of arteries with the small molecule inhibitor of mitochondrial fission, Mdivi-1 (50 μM), restricted mitochondrial dynamics and reduced proliferation. Thus, when smooth muscle is allowed to proliferate, mitochondria switch from being static to highly mobile, which may contribute to the altered calcium signalling observed in proliferative smooth muscle. Inhibiting mitochondrial mobility decreases proliferation and may be a novel target for the prevention of proliferative vascular disease.

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