A novel mechanism of regulation of cardiac contractility by mitochondrial functional state.
It is generally considered that mitochondria regulate cardiac cell contractility by providing ATP for cellular ATPases and by participating in Ca2+ homeostasis. However, other possible mechanisms by which mitochondria can influence contractility have been largely overlooked. Here, we demonstrate that inhibition of the mitochondrial electron transport chain strongly increases Ca2+-dependent and independent isometric force development in rat ventricular fibers with selectively permeabilized sarcolemma. This effect is unrelated to the ATP-generating activity of mitochondria or Ca2+ homeostasis. Furthermore, various conditions that increase K+ accumulation in the mitochondrial matrix (activation of ATP- or Ca2+-dependent K+ channels as well as inhibition of the K+ efflux pathway via the K+/H+ exchanger) induce a similar mechanical response. Modulators of mitochondrial function that augment isometric force also cause swelling of mitochondria in the vicinity of myofibrils in situ, as shown by confocal microscopy. Osmotic compression of intracellular structures abolishes the effect of mitochondria-induced force modulation, suggesting a mechanical basis for the interaction between the organelles. These findings suggest a novel mechanism for cellular regulation of myofibrillar function, whereby increases in mitochondrial volume can impose mechanical constraints inside the cell, leading to an increase in force developed by myofibrils.
U-446 INSERM, Laboratoire de Cardiologie Cellulaire et Moléculaire, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
Allen
A
Kaasik
Frederic
F
Joubert
Renée
R
Ventura-Clapier
Vladimir
V
Veksler
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001865:Bongkrekic Acid / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002451:Cell Compartmentation; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D003402:Creatine Kinase / Q000172:deficiency / Q000235:genetics; D052283:Creatine Kinase, MM Form; D052281:Creatine Kinase, Mitochondrial Form; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009210:Myofibrils / Q000502:physiology*; D009550:Nigericin / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D027961:Potassium-Hydrogen Antiporters / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D012518:Sarcomeres / Q000187:drug effects / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019810:Sodium Azide / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013314:Stress, Mechanical; D019789:Tetraethylammonium / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology; D014634:Valinomycin / Q000494:pharmacology
D001562:Benzimidazoles; D007527:Isoenzymes; D009840:Oligomycins; D027961:Potassium-Hydrogen Antiporters; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D001865:Bongkrekic Acid; D012430:Ruthenium Red; C086491:NS 1619; D014634:Valinomycin; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D002998:Clonazepam; D019789:Tetraethylammonium; D019284:Thapsigargin; C079032:CGP 37157; D020110:Pinacidil; D000255:Adenosine Triphosphate; D019810:Sodium Azide; D011803:Quinine; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form; D052281:Creatine Kinase, Mitochondrial Form; D009550:Nigericin; D011188:Potassium