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Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects.
Am J Physiol Cell Physiol. 2004 Apr; 286(4):C867-75.AJ

Abstract

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.

Authors+Show Affiliations

Department of Biology, York University, Toronto, Canada M3J IP3.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14656719

Citation

Joseph, Anna-Maria, et al. "Compensatory Responses of Protein Import and Transcription Factor Expression in Mitochondrial DNA Defects." American Journal of Physiology. Cell Physiology, vol. 286, no. 4, 2004, pp. C867-75.
Joseph AM, Rungi AA, Robinson BH, et al. Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects. Am J Physiol, Cell Physiol. 2004;286(4):C867-75.
Joseph, A. M., Rungi, A. A., Robinson, B. H., & Hood, D. A. (2004). Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects. American Journal of Physiology. Cell Physiology, 286(4), C867-75.
Joseph AM, et al. Compensatory Responses of Protein Import and Transcription Factor Expression in Mitochondrial DNA Defects. Am J Physiol, Cell Physiol. 2004;286(4):C867-75. PubMed PMID: 14656719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects. AU - Joseph,Anna-Maria, AU - Rungi,Arne A, AU - Robinson,Brian H, AU - Hood,David A, Y1 - 2003/12/03/ PY - 2003/12/6/pubmed PY - 2004/4/21/medline PY - 2003/12/6/entrez SP - C867 EP - 75 JF - American journal of physiology. Cell physiology JO - Am. J. Physiol., Cell Physiol. VL - 286 IS - 4 N2 - 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. SN - 0363-6143 UR - https://www.unboundmedicine.com/medline/citation/14656719/Compensatory_responses_of_protein_import_and_transcription_factor_expression_in_mitochondrial_DNA_defects_ L2 - http://www.physiology.org/doi/full/10.1152/ajpcell.00191.2003?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -