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PMID: 9927412 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk.

The EMBO journal ·Vol. 18 ·No. 3 ·1999-02-01 ·Pages 522-33

Biswas G, Adebanjo OA, Freedman BD, Anandatheerthavarada HK, Vijayasarathy C, Zaidi M, Kotlikoff M, Avadhani NG

Abstract

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 (Deltapsim) and electron transport-coupled ATP synthesis, which was also accompanied by an elevated steady-state cytosolic Ca2+ level ([Ca2+]i). The mitochondrial stress resulted in: (i) an enhanced expression of the sarcoplasmic reticular ryanodine receptor-1 (RyR-1), hence potentiating the Ca2+ release in response to its modulator, caffeine; (ii) enhanced levels of Ca2+-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-kappaB; and (iv) enhanced transcription of cytochrome oxidase Vb (COX Vb) subunit gene. These cellular changes, including the steady-state [Ca2+]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 [Ca2+]i changes, which are likely to be due to reduced ATP and Ca2+ efflux. Our results indicate that the mitochondrial stress signal affects a variety of cellular processes, in addition to mitochondrial membrane biogenesis.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Base Sequence Calcium Signaling Cell Line Cell Nucleus/metabolism DNA Primers/genetics DNA, Mitochondrial/genetics,metabolism Mice Mitochondria, Muscle/metabolism Muscle, Skeletal/cytology,metabolism Organelles/metabolism Ryanodine Receptor Calcium Release Channel/metabolism Stress, Physiological/genetics,metabolism Transcription Factors/metabolism
Chemicals
DNA Primers DNA, Mitochondrial Ryanodine Receptor Calcium Release Channel Transcription Factors Adenosine Triphosphate
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Biswas G
Department of Animal Biology, and the Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Adebanjo O A
Freedman B D
Anandatheerthavarada H K
Vijayasarathy C
Zaidi M
Kotlikoff M
Avadhani N G
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/18.3.522
Published
1999-02-01
Pages
522-33
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1171145
Subset
IM
Grants
NIAID NIH HHS · R01 AI060921 · United States
NIA NIH HHS · AG14917-02 · United States
NCI NIH HHS · CA-22762-21 · United States
External Links
PubMed source DOI: 10.1093/emboj/18.3.522 PMC Full Text View journal details
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