Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus

Nature Genetics
Giovanni ManfrediEric A Schon

Abstract

A T-->G transversion at nt 8993 in mitochondrial DNA of MTATP6 (encoding ATPase 6 of complex V of the respiratory chain) causes impaired mitochondrial ATP synthesis in two related mitochondrial disorders: neuropathy, ataxia and retinitis pigmentosa and maternally inherited Leigh syndrome. To overcome the biochemical defect, we expressed wildtype ATPase 6 protein allotopically from nucleus-transfected constructs encoding an amino-terminal mitochondrial targeting signal appended to a recoded ATPase 6 gene (made compatible with the universal genetic code) that also contained a carboxy-terminal FLAG epitope tag. After transfection of human cells, the precursor polypeptide was expressed, imported into and processed within mitochondria, and incorporated into complex V. Allotopic expression of stably transfected constructs in cytoplasmic hybrids (cybrids) homoplasmic with respect to the 8993T-->G mutation showed a significantly improved recovery after growth in selective medium as well as a significant increase in ATP synthesis. This is the first successful demonstration of allotopic expression of an mtDNA-encoded polypeptide in mammalian cells and could form the basis of a genetic approach to treat a number of human mitochondrial dis...Continue Reading

References

Sep 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·G IsayaL E Rosenberg
Sep 11, 1990·Nucleic Acids Research·S Mizushima, S Nagata
Mar 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·P MariottiniG Attardi
Apr 9, 1981·Nature·S AndersonI G Young
Sep 1, 1993·Annals of Neurology·D D de VriesB A van Oost
Apr 15, 1993·Biochemical and Biophysical Research Communications·Y Tatuch, B H Robinson
Jan 1, 1996·Journal of Inherited Metabolic Disease·M E Vazquez-MemijeS DiMauro
Jan 1, 1996·Methods in Enzymology·M Sciacco, E Bonilla
Feb 14, 1998·Nature·T ElstonG Oster
Mar 10, 1998·European Journal of Biochemistry·H JägerG Deckers-Hebestreit
Jul 27, 1999·American Journal of Human Genetics·S L WhiteD R Thorburn
Jan 19, 2000·Gene Therapy·P F ChinneryR N Lightowlers
May 9, 2000·Methods in Enzymology·W W HauswirthN Muzyczka
Jul 8, 2000·Brain Pathology·S DiMauro, A L Andreu
Nov 15, 2000·Biological Chemistry·A StrubW Voos
Nov 18, 2000·The Journal of Biological Chemistry·H Noji, M Yoshida
May 31, 2001·Methods in Cell Biology·G ManfrediA Naini
May 31, 2001·Methods in Cell Biology·M T RyanN Pfanner
Jul 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·M L HutcheonR L Cross
Jul 12, 2001·Antisense & Nucleic Acid Drug Development·V GeromelE Taillandier
Dec 12, 2001·Seminars in Cell & Developmental Biology·E A SchonM E Girvin

❮ Previous
Next ❯

Citations

Sep 15, 2010·Archives of Ophthalmology·Byron L LamJohn Guy
Oct 29, 2002·Annals of Neurology·John GuyAlfred S Lewin
Oct 29, 2002·Annals of Neurology·Nils-Göran Larsson
Jun 24, 2010·Journal of Inherited Metabolic Disease·Hélène Cwerman-ThibaultMarisol Corral-Debrinski
Aug 30, 2011·Journal of Inherited Metabolic Disease·An I JonckheereRichard J T Rodenburg
Dec 21, 2006·Pharmaceutical Research·Gerard G M D'SouzaVolkmar Weissig
Aug 13, 2011·Pharmaceutical Research·Volkmar Weissig
Feb 10, 2004·Progress in Retinal and Eye Research·Valerio CarelliAlfredo A Sadun
Jun 21, 2005·Molecular Genetics and Metabolism·Alexandra LatiniMoacir Wajner
Oct 17, 2003·Neuromuscular Disorders : NMD·P F ChinneryUNKNOWN Europen neuromuscular center
Jul 10, 2003·Lancet Neurology·Robert McFarlandDouglass M Turnbull
Apr 30, 2005·Nature Reviews. Genetics·Robert W Taylor, Doug M Turnbull
Aug 8, 2006·Oncogene·A ChatterjeeD Sidransky
Jun 27, 2003·The New England Journal of Medicine·Salvatore DiMauro, Eric A Schon
Mar 3, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lubica SupekovaPeter G Schultz
Mar 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Geng WangCarla M Koehler
Apr 24, 2012·Proceedings of the National Academy of Sciences of the United States of America·Hong YuJohn Guy
May 9, 2006·Antioxidants & Redox Signaling·Giorgio LenazGiancarlo Solaini
Mar 31, 2005·Rejuvenation Research·Konstantin Khrapko
May 19, 2006·Rejuvenation Research·Abhijit MukhopadhyayHenry Weiner
Sep 16, 2003·Molecular Biology of the Cell·Carl D GajewskiGiovanni Manfredi
Nov 6, 2009·Molecular Biology of the Cell·Cristofol Vives-BauzaGiovanni Manfredi
Feb 22, 2003·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·John F Allen
Nov 26, 2010·Molekuliarnaia biologiia·I O MazuninR I Sukernik
Jun 4, 2013·Annual Review of Neuroscience·José-Alain Sahel, Botond Roska
May 17, 2005·Genome Biology·Daniel O Daley, James Whelan
Nov 7, 2002·Genes & Genetic Systems·Kazuaki KitagawaChiharu Nakamura
Jul 31, 2007·PLoS Genetics·Adrian GhermanNicholas Katsanis
Jan 19, 2010·Annual Review of Pathology·Douglas C WallaceVincent Procaccio
May 20, 2008·QJM : Monthly Journal of the Association of Physicians·A M HallM R Duchen
Jan 31, 2003·Expert Opinion on Therapeutic Targets·Aubrey D N J De Grey
Mar 11, 2005·Expert Opinion on Biological Therapy·Robert W Taylor
Aug 23, 2011·Biochimica Et Biophysica Acta·David A DunnCarl A Pinkert

❮ Previous
Next ❯

Related Concepts

Related Feeds

Ataxias

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on different types of ataxias here.

Ataxia

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on ataxia here.

Ataxias (MDS)

Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on ataxia here.