Mitochondrial and endoplasmic reticulum cation fluxes: novel roles in cellular physiology
Date
2010-10-25
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Abstract
Rakusiseste katioonide, peamiselt Ca2+ ja K+, voolud mitokondrite ja sarko(endo)plasmaatilise retiikulumi (SR/ER) membraanidel mängivad olulist rolli nende toimimises. Mitokondrite põhiülesandeks on ATP tootmine ja SR/ER põhiülesandeks on rakusiseste Ca2+ voogude kontrollimine. Ehkki mitokondrid ja SR/ER on eraldiseisvad organellid, mõjutavad nad teineteist ja reguleerivad üheskoos mitmeid rakusiseseid protsesse nagu Ca2+ liikumist ja tasakaalu, erinevaid signaalradasid ja rakusurmamehhanisme. Lisaks eelmainitud protsessidele mõjutavad mitokondri maatriksis olevad katioonid (peamiselt K+) mitokondri ruumala, mis võib olla seotud teiste seni vähe-uuritud protsessidega. Samuti on probleemiks SR/ER Ca2+ voolude regulatsioon.
Hindasime, kuivõrd põhjustavad muutused katioonide voos läbi mitokondri sisemembraani mitokondrite paisumist ja millised on selle mõjud aksonaalsele transpordile neuronites ja mehhaanilistele efektidele kardiomüotsüütides. Samuti uurisime SR/ER Ca2+ voogude mõjutamist vastas-ioonide liikumise ja raku energeetilise seisundi poolt.
Töö tulemused näitavad, et mitokondrite paisumist põhjustavad ained vähendavad mitokondrite liikumist närvijätketes sõltumata ATPst. Lisaks võib see viia aksonaalse transpordi häireteni, mis võib omada rolli neurodegeneratiivsete haiguste väljakujunemisel. Leidsime ka, et mitokondrite paisumine südamelihasrakkudes in situ võib mõjutada südamelihaskiu mehhaanilisi omadusi ja põhjustada raku tuuma kompressiooni.
Samuti leidsime, et K+ ioonid mõjutavad SR/ER Ca2+ haaret. Töö tulemused lubavad oletada, et SR/ER membraanil esineb katioonide ringlus, kus K+ liikumine läbi SR/ER membraani väikese juhtivusega Ca2+-tundlike K+ kanalite ja K+/H+ vahetajate kaudu on ülioluline. Selgitasime välja ka, et südamelihasrakkude puhul toimub Ca2+ kadu sarkoplasmaatilisest retiikulumist puhkeolekus SR/ER ATP-sõltuva Ca2+ kanali kaudu, olles sõltuvuses südamelihasraku energeetilisest seisundist.
Intracellular cationic fluxes, mainly K+ and Ca2+, across membranes of mitochondria and sarco(endo)plasmic reticulum (SR/ER) play essential roles in functioning of the cell. The main function of mitochondria is production of ATP and the main function of SR/ER is controlling the intracellular Ca2+ fluxes. Although the mitochondrion and SR/ER are separated organelles, their function and functioning is tightly coupled and together they affect several intracellular processes like Ca2+ fluxes and balance, different signalling pathways and cell death mechanisms. In addition, mitochondrial volume is controlled by the cation fluxes (mainly K+) in mitochondrial matrix and changes in it can be related to other less studied processes. Also, the exact regulation mechanism of SR/ER Ca2+ fluxes is not clear. In the present study we examined how changes in cation fluxes across the inner mitochondrial membrane modulate mitochondrial swelling and what are the effects of mitochondrial swelling on axonal transport in neurons and mechanical effects of swelling on other cellular organelles in cardiomyocytes. Modulation of SR/ER Ca2+ fluxes by counter-ion fluxes and cellular energetic state was studied also. The results show that substances which cause mitochondrial swelling decrease mitochondrial motility independently from ATP. It may lead to defects of axonal transport that could have a role in development of neurodegenerative diseases. Additionally we found that mitochondrial swelling in cardiomyocytes in situ may affect the mechanical properties of cardiac fibres and could compress the nucleus. It was found that K+ ions modulate SR/ER Ca2+ uptake. Results of this study suggest that cation cycling exists on the SR/ER membrane and K+ fluxes through SR/ER small-conductance Ca2+-dependent K+ channels and K+/H+ exchangers has big importance. Also, we found that while resting energetic state regulates Ca2+ loss from sarcoplasmic reticulum throug ATP-dependent Ca2+ channel in cardiac muscle.
Intracellular cationic fluxes, mainly K+ and Ca2+, across membranes of mitochondria and sarco(endo)plasmic reticulum (SR/ER) play essential roles in functioning of the cell. The main function of mitochondria is production of ATP and the main function of SR/ER is controlling the intracellular Ca2+ fluxes. Although the mitochondrion and SR/ER are separated organelles, their function and functioning is tightly coupled and together they affect several intracellular processes like Ca2+ fluxes and balance, different signalling pathways and cell death mechanisms. In addition, mitochondrial volume is controlled by the cation fluxes (mainly K+) in mitochondrial matrix and changes in it can be related to other less studied processes. Also, the exact regulation mechanism of SR/ER Ca2+ fluxes is not clear. In the present study we examined how changes in cation fluxes across the inner mitochondrial membrane modulate mitochondrial swelling and what are the effects of mitochondrial swelling on axonal transport in neurons and mechanical effects of swelling on other cellular organelles in cardiomyocytes. Modulation of SR/ER Ca2+ fluxes by counter-ion fluxes and cellular energetic state was studied also. The results show that substances which cause mitochondrial swelling decrease mitochondrial motility independently from ATP. It may lead to defects of axonal transport that could have a role in development of neurodegenerative diseases. Additionally we found that mitochondrial swelling in cardiomyocytes in situ may affect the mechanical properties of cardiac fibres and could compress the nucleus. It was found that K+ ions modulate SR/ER Ca2+ uptake. Results of this study suggest that cation cycling exists on the SR/ER membrane and K+ fluxes through SR/ER small-conductance Ca2+-dependent K+ channels and K+/H+ exchangers has big importance. Also, we found that while resting energetic state regulates Ca2+ loss from sarcoplasmic reticulum throug ATP-dependent Ca2+ channel in cardiac muscle.
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Väitekirja elektroonilne versioon ei sisalda publikatsioone.
Keywords
doktoritööd, arstiteadus, katioonid, rakufüsioloogia