PMID- 14656719
OWN - NLM
STAT- MEDLINE
DCOM- 20040420
LR  - 20211203
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 286
IP  - 4
DP  - 2004 Apr
TI  - Compensatory responses of protein import and transcription factor expression in 
      mitochondrial DNA defects.
PG  - C867-75
AB  - Defects in mitochondrial DNA (mtDNA) evoke distinctive responses in the nuclear 
      genome, leading to altered mitochondrial biogenesis. We used C(2)C(12) cells 
      depleted of mtDNA (rho(-) cells) and fibroblasts from a mitochondrial 
      encephalopathy, lactic acidosis, and strokelike episodes (MELAS) patient to 
      examine adaptations of the protein import machinery and transcription factors 
      involved in mitochondrial biogenesis. In rho(-) cells, Tom20 and Tim23 protein 
      levels were reduced by 25% and 59%, whereas mtHSP70 was induced by twofold 
      relative to control cells. These changes were accompanied by a 21% increase in 
      enhanced yellow fluorescent protein (EYFP) import into mitochondria in rho(-) 
      cells (P < 0.05). In contrast, in MELAS cells mtHSP70 was elevated by 70%, 
      whereas Tom20 and Tom34 protein levels were increased by 45% and 112% relative to 
      control values. EYFP import was not altered in MELAS cells. In rho(-) cells, 
      protein levels of the transcription factors nuclear respiratory factor-1 (NRF-1) 
      and transcription factor A (Tfam) declined by 33% and 54%, whereas no change was 
      observed for the coactivator peroxisome proliferator receptor-gamma 
      coactivator-1alpha (PGC-1alpha). In contrast, Tfam was increased by 40% in MELAS 
      cells. Rho(-) cells displayed reduced oxygen consumption (Vo(2)) and ATP levels, 
      along with a twofold increase in lactate levels (P < 0.05). In electrically 
      stimulated C(2)C(12) cells, 109%, 78%, 60%, and 67% increases were observed in 
      mtDNA, Vo(2), cytochrome-c oxidase (COX) activity, and Tom34 levels, respectively 
      (P < 0.05). Our findings suggest that compensatory adaptations occurred to 
      maintain normal rates of protein import in response to mtDNA defects and support 
      a role for contractile activity in reducing pathophysiology associated with mtDNA 
      depletion. Because the expression of nuclear-encoded transcription factors and 
      protein import machinery components was dependent on the type of mtDNA defect, 
      these findings suggest involvement of distinct signaling cascades, each dependent 
      on the type of mitochondrial defect, resulting in divergent changes in nuclear 
      gene expression patterns.
FAU - Joseph, Anna-Maria
AU  - Joseph AM
AD  - Department of Biology, York University, Toronto, Canada M3J IP3.
FAU - Rungi, Arne A
AU  - Rungi AA
FAU - Robinson, Brian H
AU  - Robinson BH
FAU - Hood, David A
AU  - Hood DA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031203
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (High Mobility Group Proteins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Mitochondrial Membrane Transport Proteins)
RN  - 0 (Mitochondrial Precursor Protein Import Complex Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (NF-E2-Related Factor 1)
RN  - 0 (Nrf1 protein, mouse)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Nuclear Respiratory Factor 1)
RN  - 0 (Nuclear Respiratory Factors)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (TOMM20 protein, human)
RN  - 0 (TOMM34 protein, human)
RN  - 0 (Tfam protein, mouse)
RN  - 0 (Tomm20 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (XL-MTTFA protein, Xenopus)
RN  - 0 (Xenopus Proteins)
RN  - 0 (mitochondrial transcription factor A)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/genetics/metabolism
MH  - DNA, Mitochondrial/*genetics
MH  - DNA-Binding Proteins/genetics
MH  - Fibroblasts/cytology/metabolism
MH  - Gene Expression
MH  - *High Mobility Group Proteins
MH  - MELAS Syndrome/*metabolism/*physiopathology
MH  - Membrane Potentials/physiology
MH  - Membrane Transport Proteins/genetics/metabolism
MH  - Mice
MH  - *Mitochondrial Membrane Transport Proteins
MH  - Mitochondrial Precursor Protein Import Complex Proteins
MH  - *Mitochondrial Proteins
MH  - Muscle Contraction/*physiology
MH  - Muscle, Skeletal/cytology/*physiology
MH  - Myoblasts, Skeletal/cytology/metabolism
MH  - NF-E2-Related Factor 1
MH  - *Nuclear Proteins
MH  - Nuclear Respiratory Factor 1
MH  - Nuclear Respiratory Factors
MH  - Prostaglandin-Endoperoxide Synthases/metabolism
MH  - Protein Transport/physiology
MH  - Receptors, Cell Surface/genetics/metabolism
MH  - Trans-Activators/genetics
MH  - Transcription Factors/genetics
MH  - *Xenopus Proteins
EDAT- 2003/12/06 05:00
MHDA- 2004/04/21 05:00
CRDT- 2003/12/06 05:00
PHST- 2003/12/06 05:00 [pubmed]
PHST- 2004/04/21 05:00 [medline]
PHST- 2003/12/06 05:00 [entrez]
AID - 00191.2003 [pii]
AID - 10.1152/ajpcell.00191.2003 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2004 Apr;286(4):C867-75. doi: 
      10.1152/ajpcell.00191.2003. Epub 2003 Dec 3.