TNFα decreases mitochondrial movement in human airway smooth muscle.

In airway smooth muscle (ASM) cells, excitation-contraction coupling is accomplished via a cascade of events that connect an elevation of cytosolic Ca concentration ([Ca]) with cross-bridge attachment and ATP-consuming mechanical work. Excitation-energy coupling is mediated by linkage of the elevation of [Ca] to an increase in mitochondrial Ca concentration, which in turn stimulates ATP production. Proximity of mitochondria to the sarcoplasmic reticulum (SR) and plasma membrane is thought to be an important mechanism to facilitate mitochondrial Ca uptake. In this regard, mitochondrial movement in ASM cells may be key in establishing proximity. Mitochondria also move where ATP or Ca buffering is needed. Mitochondrial movement is mediated through interactions with the Miro-Milton molecular complex, which couples mitochondria to kinesin motors at microtubules. We examined mitochondrial movement in human ASM cells and hypothesized that, at basal [Ca] levels, mitochondrial movement is necessary to establish proximity of mitochondria to the SR and that, during the transient increase in [Ca] induced by agonist stimulation, mitochondrial movement is reduced, thereby promoting transient mitochondrial Ca uptake. We further hypothesized that airway inflammation disrupts basal mitochondrial movement via a reduction in Miro and Milton expression, thereby disrupting the ability of mitochondria to establish proximity to the SR and, thus, reducing transient mitochondrial Ca uptake during agonist activation. The reduced proximity of mitochondria to the SR may affect establishment of transient "hot spots" of higher [Ca] at the sites of SR Ca release that are necessary for mitochondrial Ca uptake via the mitochondrial Ca uniporter.