A mitochondrial specific stress response in mammalian cells.
Cells respond to a wide variety of stresses through the transcriptional activation of genes that harbour stress elements within their promoters. While many of these elements are shared by genes encoding proteins representative of all subcellular compartments, cells can also respond to stresses that are specific to individual organelles, such as the endoplasmic reticulum un folded protein response. Here we report on the discovery and characterization of a mitochondrial stress response in mammalian cells. We find that the accumulation of unfolded protein within the mitochondrial matrix results in the transcriptional upregulation of nuclear genes encoding mitochondrial stress proteins such as chaperonin 60, chaperonin 10, mtDnaJ and ClpP, but not those encoding stress proteins of the endoplasmic reticulum. Analysis of the chaperonin 60/10 bidirectional promoter identified a CHOP element as the mitochondrial stress response element. Dominant-negative mutant forms of CHOP and overexpression of CHOP revealed that this transcription factor, in association with C/EBPbeta, regulates expression of mitochondrial stress genes in response to the accumulation of unfolded proteins.
Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia.
Quan
Q
Zhao
Jianghui
J
Wang
Ilya V
IV
Levichkin
Stan
S
Stasinopoulos
Michael T
MT
Ryan
Nicholas J
NJ
Hoogenraad
D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D018835:Chaperonin 10 / Q000096:biosynthesis / Q000235:genetics; D018834:Chaperonin 60 / Q000096:biosynthesis / Q000235:genetics; D002522:Chlorocebus aethiops; D049071:Endopeptidase Clp; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000502:physiology*; D009954:Ornithine Carbamoyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics / Q000503:physiopathology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D018835:Chaperonin 10; D018834:Chaperonin 60; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D009954:Ornithine Carbamoyltransferase; D012697:Serine Endopeptidases; D049071:Endopeptidase Clp; D000251:Adenosine Triphosphatases