PGC-1alpha/beta Upregulation is Associated with Improved Oxidative Phosphorylation in Cells Harboring Nonsense MtDNA Mutations

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2007 Mar 8

PMID 17341490

Citations 33

Authors

Sarika Srivastava

John N Barrett

Carlos T Moraes

Affiliations

Soon will be listed here.

Abstract

We have studied the functional effects of nonsense mitochondrial DNA (mtDNA) mutations in the COXI and ND5 genes in a colorectal tumor cell line. Surprisingly, these cells had an efficient oxidative phosphorylation (OXPHOS); however, when mitochondria from these cells were transferred to an osteosarcoma nuclear background (osteosarcoma cybrids), the rate of respiration markedly declined suggesting that the phenotypic expression of the mtDNA mutations was prevented by the colorectal tumor nuclear background. We found that there was a significant increase in the steady-state levels of PGC-1alpha and PGC-1beta transcriptional coactivators in these cells and a parallel increase in the steady-state levels of several mitochondrial proteins. Accordingly, adenoviral-mediated overexpression of PGC-1alpha and PGC-1beta in the osteosarcoma cybrids stimulated mitochondrial respiration suggesting that an upregulation of PGC-1alpha/beta coactivators can partially rescue an OXPHOS defect. In conclusion, upregulation of PGC-1alpha and PGC-1beta in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on OXPHOS.

Citing Articles

A systematic review on the biochemical threshold of mitochondrial genetic variants.

Smith K, Moreira J, Wilson C, Padera J, Lamason A, Xue L Genome Res. 2024; 34(3):341-365.

PMID: 38627095 PMC: 11067886. DOI: 10.1101/gr.278200.123.

Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.

Talukdar P, Chatterji U Signal Transduct Target Ther. 2023; 8(1):427.

PMID: 37953273 PMC: 10641101. DOI: 10.1038/s41392-023-01651-w.

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels.

Mengozzi A, Costantino S, Paneni F, Duranti E, Nannipieri M, Mancini R Circ Res. 2022; 131(6):476-491.

PMID: 35968712 PMC: 9426744. DOI: 10.1161/CIRCRESAHA.122.320888.

Mitochondrial determinants of chemoresistance.

Bokil A, Sancho P Cancer Drug Resist. 2022; 2(3):634-646.

PMID: 35582564 PMC: 8992520. DOI: 10.20517/cdr.2019.46.

Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer.

De Luise M, Sollazzo M, Lama E, Coada C, Bressi L, Iorio M Sci Rep. 2022; 12(1):8020.

PMID: 35577908 PMC: 9110394. DOI: 10.1038/s41598-022-11620-y.

References

Gopalakrishnan L, Scarpulla R . Differential regulation of respiratory chain subunits by a CREB-dependent signal transduction pathway. Role of cyclic AMP in cytochrome c and COXIV gene expression. J Biol Chem. 1994; 269(1):105-13. View

Hao H, Moraes C . A disease-associated G5703A mutation in human mitochondrial DNA causes a conformational change and a marked decrease in steady-state levels of mitochondrial tRNA(Asn). Mol Cell Biol. 1997; 17(12):6831-7. PMC: 232539. DOI: 10.1128/MCB.17.12.6831. View

St-Pierre J, Drori S, Uldry M, Silvaggi J, Rhee J, Jager S . Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127(2):397-408. DOI: 10.1016/j.cell.2006.09.024. View

Villani G, Greco M, Papa S, Attardi G . Low reserve of cytochrome c oxidase capacity in vivo in the respiratory chain of a variety of human cell types. J Biol Chem. 1998; 273(48):31829-36. DOI: 10.1074/jbc.273.48.31829. View

Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman B . Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem. 2001; 277(3):1645-8. DOI: 10.1074/jbc.C100631200. View

Manfredi G, Kwong J, Oca-Cossio J, Woischnik M, Gajewski C, Martushova K . BCL-2 improves oxidative phosphorylation and modulates adenine nucleotide translocation in mitochondria of cells harboring mutant mtDNA. J Biol Chem. 2002; 278(8):5639-45. DOI: 10.1074/jbc.M203080200. View

Amuthan G, Biswas G, Zhang S, Klein-Szanto A, Vijayasarathy C, Avadhani N . Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J. 2001; 20(8):1910-20. PMC: 125420. DOI: 10.1093/emboj/20.8.1910. View

van Waveren C, Sun Y, Cheung H, Moraes C . Oxidative phosphorylation dysfunction modulates expression of extracellular matrix--remodeling genes and invasion. Carcinogenesis. 2005; 27(3):409-18. PMC: 2778475. DOI: 10.1093/carcin/bgi242. View

Liu V, Shi H, Cheung A, Chiu P, Leung T, Nagley P . High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res. 2001; 61(16):5998-6001. View

10.

Woischnik M, Moraes C . Pattern of organization of human mitochondrial pseudogenes in the nuclear genome. Genome Res. 2002; 12(6):885-93. PMC: 1383742. DOI: 10.1101/gr.227202. View

11.

Yoon J, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J . Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001; 413(6852):131-8. DOI: 10.1038/35093050. View

12.

Gleyzer N, Vercauteren K, Scarpulla R . Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol. 2005; 25(4):1354-66. PMC: 548005. DOI: 10.1128/MCB.25.4.1354-1366.2005. View

13.

Vander Heiden M, Li X, Gottleib E, Hill R, Thompson C, Colombini M . Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem. 2001; 276(22):19414-9. DOI: 10.1074/jbc.M101590200. View

14.

Pani G, Colavitti R, Borrello S, Galeotti T . Endogenous oxygen radicals modulate protein tyrosine phosphorylation and JNK-1 activation in lectin-stimulated thymocytes. Biochem J. 2000; 347 Pt 1:173-81. PMC: 1220945. View

15.

Lin J, Wu H, Tarr P, Zhang C, Wu Z, Boss O . Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002; 418(6899):797-801. DOI: 10.1038/nature00904. View

16.

Hanna M, Nelson I, Rahman S, Lane R, Land J, Heales S . Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA. Am J Hum Genet. 1998; 63(1):29-36. PMC: 1377234. DOI: 10.1086/301910. View

17.

Mashkevich G, Repetto B, Glerum D, Jin C, Tzagoloff A . SHY1, the yeast homolog of the mammalian SURF-1 gene, encodes a mitochondrial protein required for respiration. J Biol Chem. 1997; 272(22):14356-64. DOI: 10.1074/jbc.272.22.14356. View

18.

Chomyn A . In vivo labeling and analysis of human mitochondrial translation products. Methods Enzymol. 1996; 264:197-211. DOI: 10.1016/s0076-6879(96)64020-8. View

19.

Bai Y, Shakeley R, Attardi G . Tight control of respiration by NADH dehydrogenase ND5 subunit gene expression in mouse mitochondria. Mol Cell Biol. 2000; 20(3):805-15. PMC: 85197. DOI: 10.1128/MCB.20.3.805-815.2000. View

20.

Hao H, Morrison L, Moraes C . Suppression of a mitochondrial tRNA gene mutation phenotype associated with changes in the nuclear background. Hum Mol Genet. 1999; 8(6):1117-24. DOI: 10.1093/hmg/8.6.1117. View