Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.
Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.
‡Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
Jessica L
JL
Fetterman
Blake R
BR
Zelickson
Larry W
LW
Johnson
Douglas R
DR
Moellering
David G
DG
Westbrook
Melissa
M
Pompilius
Melissa J
MJ
Sammy
Michelle
M
Johnson
Kimberly J
KJ
Dunham-Snary
Xuemei
X
Cao
Wayne E
WE
Bradley
Jinju
J
Zhang
Chih-Chang
CC
Wei
Balu
B
Chacko
Theodore G
TG
Schurr
Robert A
RA
Kesterson
Louis J
LJ
Dell'italia
Victor M
VM
Darley-Usmar
Danny R
DR
Welch
Scott W
SW
Ballinger
D000818:Animals; D002306:Cardiac Volume / Q000235:genetics*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism; D020022:Genetic Predisposition to Disease; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D009245:NADH Dehydrogenase