McManus 2015 Abstract MiP2015

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The etiology of age-dependent disease: a story of two genomes.

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McManus MJ, Chen HW, Picard M, Potluri P, Morrow R, Angelin A, Narula J, Wallace DC (2015)

Event: MiP2015

If decreased mitochondrial vitality drives aging, then the hereditary anomalies of agerelated disease may be explained by the complex interaction between the Mendelian and non-Mendelian mitochondrial genes, which together determine mitochondrial function. To investigate this hypothesis, we analyzed the relative importance of mtDNA and nDNA mutations in heart disease, the number one cause of mortality in the US. We first examined a 13-generation Mennonite pedigree with autosomal recessive cardiomyopathy due a mutation in the mitochondrial adenine nucleotide translocator-1 (ANT1). Substantial variability in the progression of heart disease segregated with maternal lineage, and the severity of cardiomyopathy correlated with the mtDNA haplogroups [1]. To determine the causative nature of this correlation, we examined the influence of inherited mtDNA mutations on ANT1-cardiomyopathy in the mouse. We introduced homoplasmic mtDNA ND6 or COI missense mutations into the mouse female germ line, generating mice with complex I or IV deficiency, respectively, and analyzed Ant1-dependent cardiomyopathy on the different mtDNA backgrounds. On wt mtDNA background, the Ant1-/- mice developed a distinctive concentric dilated cardiomyopathy, characterized by substantial myocardial hypertrophy, ventricular dilation and shortened lifespan. Loss of ANT1 impaired F0F1ATPase assembly and prevented dimerization, leading to “kinky” cristae architecture. The mtDNA ND6 mutation accelerated Ant1-/- age-dependent cardiomyopathy, as evidenced by increased ultrastructrural abnormalities, bioenergetic defects, sensitized mitochondrial permeability transition, increased mtDNA damage, and heart failure that ultimately attenuated the lifespan. Our results are the first to prove the cause-and-effect relationship between mtDNA variation and the penetrance of age-related disease and mortality in mammals.


O2k-Network Lab: CA Montreal Hepple RT, US PA Philadelphia Wallace DC


Labels: MiParea: mtDNA;mt-genetics, nDNA;cell genetics  Pathology: Aging;senescence, Cardiovascular 

Organism: Human 


Enzyme: Complex I, Complex IV;cytochrome c oxidase 



Event: A1, Oral  MiP2015 

Affiliations

1-Children's Hospital Philadelphia, Dept Pathology, Center for Mitoch Epigenomic Med (CMEM), Colket Translational Research Building, Philadelphia, PA; 2-Mt Sinai Hospital, The Lauder Family Cardiovascular Ambulatory Center, New York, NY, USA. - meaganjm@gmail.com

References and acknowledgements

  1. Strauss KA, DuBiner L, Simon M, Zaragoza M, Sengupta PP, Li P, Narula N, Dreike S, Platt J, Procaccio V, Ortiz-González XR, Puffenberger EG, Kelley RI, Morton DH, Narula J, Wallace DC (2013) Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup. Proc Natl Acad Sci U S A 110:3453-8.