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Retrograde Ca 2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter‐organelle crosstalk
Author(s) -
Biswas Gopa,
Adebanjo Olugbenga A.,
Freedman Bruce D.,
Anandatheerthavarada Hindupur K.,
Vijayasarathy C.,
Zaidi Mone,
Kotlikoff Michael,
Avadhani Narayan G.
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.3.522
Subject(s) - biology , crosstalk , c2c12 , microbiology and biotechnology , organelle , myocyte , mitochondrion , skeletal muscle , signal transduction , retrograde signaling , anatomy , myogenesis , physics , optics
We have investigated the mechanism of mitochondrial–nuclear crosstalk during cellular stress in mouse C2C12 myocytes. For this purpose, we used cells with reduced mitochondrial DNA (mtDNA) contents by ethidium bromide treatment or myocytes treated with known mitochondrial metabolic inhibitors, including carbonyl cyanide m ‐chlorophenylhydrazone (CCCP), antimycin, valinomycin and azide. Both genetic and metabolic stresses similarly affected mitochondrial membrane potential (Δψ m ) and electron transport‐coupled ATP synthesis, which was also accompanied by an elevated steady‐state cytosolic Ca 2+ level ([Ca 2+ ] i ). The mitochondrial stress resulted in: (i) an enhanced expression of the sarcoplasmic reticular ryanodine receptor‐1 (RyR‐1), hence potentiating the Ca 2+ release in response to its modulator, caffeine; (ii) enhanced levels of Ca 2+ ‐responsive factors calineurin, calcineurin‐dependent NFATc (cytosolic counterpart of activated T‐cell‐specific nuclear factor) and c‐Jun N‐terminal kinase (JNK)‐dependent ATF2 (activated transcription factor 2); (iii) reduced levels of transcription factor, NF‐κB; and (iv) enhanced transcription of cytochrome oxidase Vb ( COX Vb ) subunit gene. These cellular changes, including the steady‐state [Ca 2+ ] i were normalized in genetically reverted cells which contain near‐normal mtDNA levels. We propose that the mitochondria‐to‐nucleus stress signaling occurs through cytosolic [Ca 2+ ] i changes, which are likely to be due to reduced ATP and Ca 2+ efflux. Our results indicate that the mitochondrial stress signal affects a variety of cellular processes, in addition to mitochondrial membrane biogenesis.