TY - JOUR
T1 - TNFα decreases mitochondrial movement in human airway smooth muscle
AU - Delmotte, Philippe
AU - Zavaletta, Vanessa A.
AU - Thompson, Michael A.
AU - Prakash, Y. S.
AU - Sieck, Gary C.
N1 - Publisher Copyright:
© 2017 the American Physiological Society.
PY - 2017
Y1 - 2017
N2 - In airway smooth muscle (ASM) cells, excitation-contraction coupling is accomplished via a cascade of events that connect an elevation of cytosolic Ca2+ concentration ([Ca2+]cyt) with cross-bridge attachment and ATP-consuming mechanical work. Excitation-energy coupling is mediated by linkage of the elevation of [Ca2+]cyt to an increase in mitochondrial Ca2+ 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 Ca2+ uptake. In this regard, mitochondrial movement in ASM cells may be key in establishing proximity. Mitochondria also move where ATP or Ca2+ 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 [Ca2+]cyt levels, mitochondrial movement is necessary to establish proximity of mitochondria to the SR and that, during the transient increase in [Ca2+]cyt induced by agonist stimulation, mitochondrial movement is reduced, thereby promoting transient mitochondrial Ca2+ 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 Ca2+ uptake during agonist activation. The reduced proximity of mitochondria to the SR may affect establishment of transient “hot spots” of higher [Ca2+]cyt at the sites of SR Ca2+ release that are necessary for mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter.
AB - In airway smooth muscle (ASM) cells, excitation-contraction coupling is accomplished via a cascade of events that connect an elevation of cytosolic Ca2+ concentration ([Ca2+]cyt) with cross-bridge attachment and ATP-consuming mechanical work. Excitation-energy coupling is mediated by linkage of the elevation of [Ca2+]cyt to an increase in mitochondrial Ca2+ 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 Ca2+ uptake. In this regard, mitochondrial movement in ASM cells may be key in establishing proximity. Mitochondria also move where ATP or Ca2+ 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 [Ca2+]cyt levels, mitochondrial movement is necessary to establish proximity of mitochondria to the SR and that, during the transient increase in [Ca2+]cyt induced by agonist stimulation, mitochondrial movement is reduced, thereby promoting transient mitochondrial Ca2+ 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 Ca2+ uptake during agonist activation. The reduced proximity of mitochondria to the SR may affect establishment of transient “hot spots” of higher [Ca2+]cyt at the sites of SR Ca2+ release that are necessary for mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter.
KW - Airway
KW - Asthma
KW - Milton
KW - Miro
KW - Mitochondria
KW - TNFα
UR - http://www.scopus.com/inward/record.url?scp=85021845085&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021845085&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00538.2016
DO - 10.1152/ajplung.00538.2016
M3 - Article
C2 - 28473328
AN - SCOPUS:85021845085
SN - 1040-0605
VL - 313
SP - L166-L176
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 1
ER -