Picard 2014 Abstract MiP2014

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Quantitative regulation of nuclear gene expression by mitochondrial DNA heteroplasmy.
Picard M
Mitochondr Physiol Network 19.13 - MiP2014

Picard M, Zhang J, Hancock S, Derbeneva O, Golhar R, Golik P, O’Hearn S, Levy SE, Potluri P, Lvova M, Davila A, Lin CS, Perin JC, Rappaport EF, Hakonarson H, Trounce I, Procaccio V, Wallace DC (2014)

Event: MiP2014

Mitochondrial disorders caused by mtDNA mutations result in heterogeneous and organ-specific symptoms, but the cellular basis for this phenomenon is unknown [1]. Beyond a central role in energy production, mitochondrial metabolism involves key molecular substrates that modify transcriptional processes and the epigenome, suggesting that mitochondria actively regulate nuclear gene expression in complex ways [2]. To address this question, we introduced different proportions of normal and mutant mitochondrial DNA (termed heteroplasmy) of the most common human pathogenic mtDNA point mutation (tRNALeu(UUR) 3243A>G) [3] to a series of human syngenic cybrid cell lines. Increasing mutation load from 0 to 100% resulted in a progressive loss of electron transfer-pathway subunits and a range of respiratory system impairment from mild to severe. In contrast, RNA sequencing revealed broad genome-wide expression profiles and specific functional pathways strongly affected in a dose-response, but biphasic manner. These notably included chromatin components such as histone variants, chromatin-remodeling factors of the SWI/SNF family and the DNA methyltransferases.

Likewise, mtDNA transcript levels were modified, following a similar bi-phasic pattern. Gene ontology and functional pathway analysis indicated that, consistent with clinical disease presentation, mild bioenergetic defects mainly downregulated gene families associated with energy metabolism and intracellular signaling, whereas more severe bioenergetic defects activated distinct non-overlapping pathways previously associated with neurodegeneration. Increasing heteroplasmy levels also modified cellular and nuclear volumes, mitochondrial morphology and ultrastructure, and mtDNA copy number. Thus, the same mtDNA mutation can result in a multifinality of cellular and transcriptional phenotypes, depending upon its intracellular levels. Overall, these data establish that even mild mitochondrial defects triggered by mtDNA heteroplasmy induce broad transcriptional changes throughout the nuclear genome. This, along with cell-specific, may contribute to explain the heterogeneous and organ-specific nature of mitochondrial disorders.

O2k-Network Lab: US PA Philadelphia Wallace DC

Labels: MiParea: mtDNA;mt-genetics, mt-Medicine, Patients 

Tissue;cell: Other cell lines 

Event: A1, Oral  MiP2014 


1-Center Mitoch Epigenomic Med; 2-School Biol Sc, Univ Hong Kong, PRC; 3-Trovagene, 11055 Flintkote Ave, San Diego, USA; 4-Center Applied Genomics, Div Genetics, Dep Pediatrics; 5-Inst Genetics Biotech, Warsaw Univ, Poland; 6-Morton Mower Central Research Lab, Sinai Hospital Baltimore, USA; 7-Genomics Services Lab, HudsonAlpha Inst Biotech, Huntsville, USA; 8-Nucleic Acid/Protein Research Core Facility; 9-Centre Eye Research Australia, Royal Victorian Eye Ear Hospital, Melbourne, Australia; 10-Dep Biochem Genet, Nat Center Neurodegenerative Mitochon diseases, CHU Angers, France; 1,4,8-Children’s Hospital Philadelphia, USA. - PicardM@email.chop.edu

References and acknowledgements

This work was supported by: NIH, Simons Foundation.

  1. Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev Genet 6: 389-402.
  2. Wallace DC, Fan W. (2010) Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10: 12–31.
  3. Hämäläinen RH, Manninen T, Koivumäki H, Kislin M, Otonkoski T, Suomalainen A (2013) Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model. Proc Natl Acad Sci USA 110: 3622-30.