{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:46:51Z","timestamp":1787017611166,"version":"build-2736575974"},"reference-count":40,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2004,4]]},"abstract":"<jats:p>\n                    Defects in mitochondrial DNA (mtDNA) evoke distinctive responses in the nuclear genome, leading to altered mitochondrial biogenesis. We used C\n                    <jats:sub>2<\/jats:sub>\n                    C\n                    <jats:sub>12<\/jats:sub>\n                    cells depleted of mtDNA (rho\n                    <jats:sup>\u2013<\/jats:sup>\n                    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\n                    <jats:sup>\u2013<\/jats:sup>\n                    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\n                    <jats:sup>\u2013<\/jats:sup>\n                    cells ( P &lt; 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\n                    <jats:sup>\u2013<\/jats:sup>\n                    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-\u03b3 coactivator-1\u03b1 (PGC-1\u03b1). In contrast, Tfam was increased by 40% in MELAS cells. Rho\n                    <jats:sup>\u2013<\/jats:sup>\n                    cells displayed reduced oxygen consumption (V\u0307o\n                    <jats:sub>2<\/jats:sub>\n                    ) and ATP levels, along with a twofold increase in lactate levels ( P &lt; 0.05). In electrically stimulated C\n                    <jats:sub>2<\/jats:sub>\n                    C\n                    <jats:sub>12<\/jats:sub>\n                    cells, 109%, 78%, 60%, and 67% increases were observed in mtDNA, V\u0307o\n                    <jats:sub>2<\/jats:sub>\n                    , cytochrome- c oxidase (COX) activity, and Tom34 levels, respectively ( P &lt; 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.\n                  <\/jats:p>","DOI":"10.1152\/ajpcell.00191.2003","type":"journal-article","created":{"date-parts":[[2004,3,4]],"date-time":"2004-03-04T13:07:45Z","timestamp":1078405665000},"page":"C867-C875","source":"Crossref","is-referenced-by-count":63,"title":["Compensatory responses of protein import and transcription factor expression in mitochondrial DNA defects"],"prefix":"10.1152","volume":"286","author":[{"given":"Anna-Maria","family":"Joseph","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne A.","family":"Rungi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Hood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","doi-asserted-by":"crossref","unstructured":"Arnould T\n                      , Vankoningsloo S, Renard P, Houbion A, Ninane A, Remacle J, and Raes M.\n                      CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation.\n                      EMBO J\n                      21\n                      : 53\u201363, 2002.","DOI":"10.1093\/emboj\/21.1.53"},{"key":"REF2","doi-asserted-by":"crossref","unstructured":"Biswas G\n                      , Adebanjo OA, Freedman BD, Anandatheerthavarada HK, Vijayasarathy C, Zaidi M, Kotlikoff M, and Avadhani NG.\n                      Retrograde Ca\n                      2+\n                      signaling in C\n                      2\n                      C\n                      12\n                      skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk.\n                      EMBO J\n                      18\n                      : 522\u2013533, 1999.","DOI":"10.1093\/emboj\/18.3.522"},{"key":"REF3","doi-asserted-by":"crossref","unstructured":"Borner GV\n                      , Zeviani M, Tiranti V, Carrara F, Hoffmann S, Gerbitz KD, Lochmuller H, Pongratz D, Klopstock T, Melberg A, Holme E, and Paabo S.\n                      Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients.\n                      Hum Mol Genet\n                      9\n                      : 467\u2013475, 2000.","DOI":"10.1093\/hmg\/9.4.467"},{"key":"REF4","doi-asserted-by":"crossref","unstructured":"Boudreau-Lariviere C\n                      , Parry DJ, and Jasmin BJ.\n                      Myotubes originating from single fast and slow satellite cells display similar patterns of AChE expression.\n                      Am J Physiol Regul Integr Comp Physiol\n                      278\n                      : R140\u2013R148, 2000.","DOI":"10.1152\/ajpregu.2000.278.1.R140"},{"key":"REF5","doi-asserted-by":"crossref","unstructured":"Chewawiwat N\n                      , Yano M, Terada K, Hoogenraad NJ, and Mori M.\n                      Characterization of the novel mitochondrial protein import component, Tom34, in mammalian cells.\n                      J Biochem (Tokyo)\n                      125\n                      : 721\u2013727, 1999.","DOI":"10.1093\/oxfordjournals.jbchem.a022342"},{"key":"REF6","doi-asserted-by":"crossref","unstructured":"Colavecchia M\n                      , Christie LN, Kanwar YS, and Hood DA.\n                      Functional consequences of thyroid hormone-induced changes in the mitochondrial protein import pathway.\n                      Am J Physiol Endocrinol Metab\n                      284\n                      : E29\u2013E35, 2003.","DOI":"10.1152\/ajpendo.00294.2002"},{"key":"REF7","doi-asserted-by":"crossref","unstructured":"Connor MK\n                      , Irrcher I, and Hood DA.\n                      Contractile activity-induced transcriptional activation of cytochrome C involves Sp1 and is proportional to mitochondrial ATP synthesis in C\n                      2\n                      C\n                      12\n                      muscle cells.\n                      J Biol Chem\n                      276\n                      : 15898\u201315904, 2001.","DOI":"10.1074\/jbc.M100272200"},{"key":"REF8","doi-asserted-by":"crossref","unstructured":"Craig EE\n                      , Chesley A, and Hood DA.\n                      Thyroid hormone modifies mitochondrial phenotype by increasing protein import without altering degradation.\n                      Am J Physiol Cell Physiol\n                      275\n                      : C1508\u2013C1515, 1998.","DOI":"10.1152\/ajpcell.1998.275.6.C1508"},{"key":"REF9","doi-asserted-by":"crossref","unstructured":"Desjardins P\n                      , Frost E, and Morais R.\n                      Ethidium bromide-induced loss of mitochondrial DNA from primary chicken embryo fibroblasts.\n                      Mol Cell Biol\n                      5\n                      : 1163\u20131169, 1985.","DOI":"10.1128\/MCB.5.5.1163"},{"key":"REF10","doi-asserted-by":"crossref","unstructured":"Gilkerson RW\n                      , Margineantu DH, Capaldi RA, and Selker JM.\n                      Mitochondrial DNA depletion causes morphological changes in the mitochondrial reticulum of cultured human cells.\n                      FEBS Lett\n                      474\n                      : 1\u20134, 2000.","DOI":"10.1016\/S0014-5793(00)01527-1"},{"key":"REF11","doi-asserted-by":"crossref","unstructured":"Glick BS\n                      , Wachter C, Reid GA, and Schatz G.\n                      Import of cytochrome b2 to the mitochondrial intermembrane space: the tightly folded heme-binding domain makes import dependent upon matrix ATP.\n                      Protein Sci\n                      2\n                      : 1901\u20131917, 1993.","DOI":"10.1002\/pro.5560021112"},{"key":"REF12","doi-asserted-by":"crossref","unstructured":"Goto Y\n                      , Nonaka I, and Horai S.\n                      A mutation in the tRNA\n                      Leu(UUR)\n                      gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.\n                      Nature\n                      348\n                      : 651\u2013653, 1990.","DOI":"10.1038\/348651a0"},{"key":"REF13","doi-asserted-by":"crossref","unstructured":"Grey JY\n                      , Connor MK, Gordon JW, Yano M, Mori M, and Hood DA.\n                      Tom20-mediated mitochondrial protein import in intact muscle cells during differentiation.\n                      Am J Physiol Cell Physiol\n                      279\n                      : C1393\u2013C1400, 2000.","DOI":"10.1152\/ajpcell.2000.279.5.C1393"},{"key":"REF14","doi-asserted-by":"crossref","unstructured":"Hofmann S\n                      , Rothbauer U, M\u00fchlenbein N, Neupert W, Gerbitz KD, Brunner M, and Bauer MF.\n                      The C66W mutation in the deafness and dystonia peptide 1 (DDP1) affects the formation of functional DDP1\u00b7TIM13 complexes in the mitochondrial intermembrane space.\n                      J Biol Chem\n                      277\n                      : 23287\u201323293, 2002.","DOI":"10.1074\/jbc.M201154200"},{"key":"REF15","doi-asserted-by":"crossref","unstructured":"Hoogenraad NJ\n                      , Ward LA, and Ryan MT.\n                      Import and assembly of proteins into mitochondria of mammalian cells.\n                      Biochim Biophys Acta\n                      1592\n                      : 97\u2013105, 2002.","DOI":"10.1016\/S0167-4889(02)00268-9"},{"key":"REF16","doi-asserted-by":"crossref","unstructured":"Huckriede A\n                      and Agsteribbe E.\n                      Decreased synthesis and inefficient mitochondrial import of Hsp60 in a patient with a mitochondrial encephalomyopathy.\n                      Biochim Biophys Acta\n                      1227\n                      : 200\u2013206, 1994.","DOI":"10.1016\/0925-4439(94)90096-5"},{"key":"REF17","doi-asserted-by":"crossref","unstructured":"Huo L\n                      and Scarpulla RC.\n                      Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice.\n                      Mol Cell Biol\n                      21\n                      : 644\u2013654, 2001.","DOI":"10.1128\/MCB.21.2.644-654.2001"},{"key":"REF18","doi-asserted-by":"crossref","unstructured":"Inoue K\n                      , Ito S, Takai D, Soejima A, Shisa H, LePecq JB, Segal-Bendirdjian E, Kagawa Y, and Hayashi JI.\n                      Isolation of mitochondrial DNA-less mouse cell lines and their application for trapping mouse synaptosomal mitochondrial DNA with deletion mutations.\n                      J Biol Chem\n                      272\n                      : 15510\u201315515, 1997.","DOI":"10.1074\/jbc.272.24.15510"},{"key":"REF19","doi-asserted-by":"crossref","unstructured":"Irrcher I\n                      , Adhihetty PJ, Sheehan T, Joseph AM, and Hood DA.\n                      PPAR\u03b3 coactivator-1\u03b1 expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations.\n                      Am J Physiol Cell Physiol\n                      284\n                      : C1669\u2013C1677, 2003.","DOI":"10.1152\/ajpcell.00409.2002"},{"key":"REF20","doi-asserted-by":"crossref","unstructured":"Koehler CM\n                      , Leuenberger D, Merchant S, Renold A, Junne T, and Schatz G.\n                      Human deafness dystonia syndrome is a mitochondrial disease.\n                      Proc Natl Acad Sci USA\n                      96\n                      : 2141\u20132146, 1999.","DOI":"10.1073\/pnas.96.5.2141"},{"key":"REF21","doi-asserted-by":"crossref","unstructured":"Larsson NG\n                      and Oldfors A.\n                      Mitochondrial myopathies.\n                      Acta Physiol Scand\n                      171\n                      : 385\u2013393, 2001.","DOI":"10.1046\/j.1365-201x.2001.00842.x"},{"key":"REF22","doi-asserted-by":"crossref","unstructured":"Larsson NG\n                      , Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, Barsh GS, and Clayton DA.\n                      Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice.\n                      Nat Genet\n                      18\n                      : 231\u2013236, 1998.","DOI":"10.1038\/ng0398-231"},{"key":"REF23","doi-asserted-by":"crossref","unstructured":"Lehman JJ\n                      , Barger PM, Kovacs A, Saffitz JE, Medeiros DM, and Kelly DP.\n                      Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis.\n                      J Clin Invest\n                      106\n                      : 847\u2013856, 2000.","DOI":"10.1172\/JCI10268"},{"key":"REF24","doi-asserted-by":"crossref","unstructured":"Li B\n                      , Holloszy JO, and Semenkovich CF.\n                      Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells.\n                      J Biol Chem\n                      274\n                      : 17534\u201317540, 1999.","DOI":"10.1074\/jbc.274.25.17534"},{"key":"REF25","doi-asserted-by":"crossref","unstructured":"Li K\n                      , Neufer PD, and Williams RS.\n                      Nuclear responses to depletion of mitochondrial DNA in human cells.\n                      Am J Physiol Cell Physiol\n                      269\n                      : C1265\u2013C1270, 1995.","DOI":"10.1152\/ajpcell.1995.269.5.C1265"},{"key":"REF26","doi-asserted-by":"crossref","unstructured":"Marusich MF\n                      , Robinson BH, Taanman JW, Kim SJ, Schillace R, Smith JL, and Capaldi RA.\n                      Expression of mtDNA and nDNA encoded respiratory chain proteins in chemically and genetically-derived Rho0 human fibroblasts: a comparison of subunit proteins in normal fibroblasts treated with ethidium bromide and fibroblasts from a patient with mtDNA depletion syndrome.\n                      Biochim Biophys Acta\n                      1362\n                      : 145\u2013159, 1997.","DOI":"10.1016\/S0925-4439(97)00061-6"},{"key":"REF27","doi-asserted-by":"crossref","unstructured":"Miranda S\n                      , Foncea R, Guerrero J, and Leighton F.\n                      Oxidative stress and upregulation of mitochondrial biogenesis genes in mitochondrial DNA-depleted HeLa cells.\n                      Biochem Biophys Res Commun\n                      258\n                      : 44\u201349, 1999.","DOI":"10.1006\/bbrc.1999.0580"},{"key":"REF28","doi-asserted-by":"crossref","unstructured":"Moudy AM\n                      , Handran SD, Goldberg MP, Ruffin N, Karl I, Kranz-Eble P, DeVivo DC, and Rothman SM.\n                      Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy.\n                      Proc Natl Acad Sci USA\n                      92\n                      : 729\u2013733, 1995.","DOI":"10.1073\/pnas.92.3.729"},{"key":"REF29","doi-asserted-by":"crossref","unstructured":"Murakami T\n                      , Shimomura Y, Yoshimura A, Sokabe M, and Fujitsuka N.\n                      Induction of nuclear respiratory factor-1 expression by an acute bout of exercise in rat muscle.\n                      Biochim Biophys Acta\n                      1381\n                      : 113\u2013122, 1998.","DOI":"10.1016\/S0304-4165(98)00018-X"},{"key":"REF30","doi-asserted-by":"crossref","unstructured":"Rungi AA\n                      , Primeau A, Christie LN, Gordon JW, Robinson BH, and Hood DA.\n                      Events upstream of mitochondrial protein import limit the oxidative capacity of fibroblasts in multiple mitochondrial disease.\n                      Biochim Biophys Acta\n                      1586\n                      : 146\u2013154, 2002.","DOI":"10.1016\/S0925-4439(01)00072-2"},{"key":"REF31","doi-asserted-by":"crossref","unstructured":"Scarpulla RC\n                      .\n                      Nuclear activators and coactivators in mammalian mitochondrial biogenesis.\n                      Biochim Biophys Acta\n                      1576\n                      : 1\u201314, 2002.","DOI":"10.1016\/S0167-4781(02)00343-3"},{"key":"REF32","doi-asserted-by":"crossref","unstructured":"Taivassalo T\n                      , Abbott A, Wyrick P, and Haller RG.\n                      Venous oxygen levels during aerobic forearm exercise: an index of impaired oxidative metabolism in mitochondrial myopathy.\n                      Ann Neurol\n                      51\n                      : 38\u201344, 2002.","DOI":"10.1002\/ana.10027"},{"key":"REF33","doi-asserted-by":"crossref","unstructured":"Taivassalo T\n                      , Shoubridge EA, Chen J, Kennaway NG, DiMauro S, Arnold DL, and Haller RG.\n                      Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects.\n                      Ann Neurol\n                      50\n                      : 133\u2013141, 2001.","DOI":"10.1002\/ana.1050"},{"key":"REF34","doi-asserted-by":"crossref","unstructured":"Takahashi M\n                      , Chesley A, Freyssenet D, and Hood DA.\n                      Contractile activity-induced adaptations in the mitochondrial protein import system.\n                      Am J Physiol Cell Physiol\n                      274\n                      : C1380\u2013C1387, 1998.","DOI":"10.1152\/ajpcell.1998.274.5.C1380"},{"key":"REF35","doi-asserted-by":"crossref","unstructured":"Voisine C\n                      , Craig EA, Zufall N, von Ahsen O, Pfanner N, and Voos W.\n                      The protein import motor of mitochondria: unfolding and trapping of preproteins are distinct and separable functions of matrix Hsp70.\n                      Cell\n                      97\n                      : 565\u2013574, 1999.","DOI":"10.1016\/S0092-8674(00)80768-0"},{"key":"REF36","doi-asserted-by":"crossref","unstructured":"Wallace DC\n                      .\n                      Mouse models for mitochondrial disease.\n                      Am J Med Genet\n                      106\n                      : 71\u201393, 2001.","DOI":"10.1002\/ajmg.1393"},{"key":"REF37","doi-asserted-by":"crossref","unstructured":"Wasniewska M\n                      , Karczmarewicz E, Pronicki M, Piekutowska-Abramczuk D, Zablocki K, Popowska E, Pronicka E, and Duszynski J.\n                      Abnormal calcium homeostasis in fibroblasts from patients with Leigh disease.\n                      Biochem Biophys Res Commun\n                      283\n                      : 687\u2013693, 2001.","DOI":"10.1006\/bbrc.2001.4834"},{"key":"REF38","doi-asserted-by":"crossref","unstructured":"Williams RS\n                      , Salmons S, Newsholme EA, Kaufman RE, and Mellor J.\n                      Regulation of nuclear and mitochondrial gene expression by contractile activity in skeletal muscle.\n                      J Biol Chem\n                      261\n                      : 376\u2013380, 1986.","DOI":"10.1016\/S0021-9258(17)42482-3"},{"key":"REF39","doi-asserted-by":"crossref","unstructured":"Wu Z\n                      , Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha A, Troy A, Cinti S, Lowell B, Scarpulla RC, and Spiegelman BM.\n                      Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.\n                      Cell\n                      98\n                      : 115\u2013124, 1999.","DOI":"10.1016\/S0092-8674(00)80611-X"},{"key":"REF40","doi-asserted-by":"crossref","unstructured":"Yano M\n                      , Kanazawa M, Terada K, Namchai C, Yamaizumi M, Hanson B, Hoogenraad N, and Mori M.\n                      Visualization of mitochondrial protein import in cultured mammalian cells with green fluorescent protein and effects of overexpression of the human import receptor Tom20.\n                      J Biol Chem\n                      272\n                      : 8459\u20138465, 1997.","DOI":"10.1074\/jbc.272.13.8459"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00191.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T14:50:37Z","timestamp":1718635837000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00191.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,4]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2004,4]]}},"alternative-id":["10.1152\/ajpcell.00191.2003"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00191.2003","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,4]]}}}