TY - JOUR
T1 - Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts
AU - Holzem, Katherine M.
AU - Vinnakota, Kalyan C.
AU - Ravikumar, Vinod K.
AU - Madden, Eli J.
AU - Ewald, Gregory A.
AU - Dikranian, Krikor
AU - Beard, Daniel A.
AU - Efimov, Igor R.
N1 - Funding Information:
The authors thank the surgical teams at Barnes-Jewish Hospital and Mid-America Transplant Services for their assistance with human heart procurement, most notably Drs. Scott Silvestry and Michael Pasque. The authors recognize the Translational Cardiovascular Biobank and Repository (Washington University in St. Louis), which is supported by the U.S. National Institutes of Health (NIH) Clinical and Translational Science Awards program (Grant UL1TR000448), and the Richard J. Wilkinson Trust, for the provision of patient records. The authors also recognize the Nutrition and Obesity Research Center for the use of their Orobos Oxygraph-O2k, and the laboratories of Jan Bieschke and Jeanne Nerbonne for the use of the NanoPhotometer P-Class and 7900HT equipment, respectively. The authors thank Marlyn Levy (Washington University Department of Cell Biology and Physiology Electron Microscopy Facility) for processing samples. This work was supported by the NIH National Heart, Lung, and Blood Institute [Grants R01HL114395 and F30HL114310 (to K.H.)], and by the American Heart Association [Grant 12PRE12050315 (to K.H.)]. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2016/8
Y1 - 2016/8
N2 - During human heart failure, the balance of cardiac energy use switches from predominantly fatty acids (FAs) to glucose. We hypothesized that this substrate shift was the result of mitochondrial degeneration; therefore, we examined mitochondrial oxidation and ultrastructure in the failing human heart by using respirometry, transmission electron microscopy, and gene expression studies of demographically matched donor and failing human heart left ventricular (LV) tissues. Surprisingly, respiratory capacities for failing LV isolated mitochondria (n = 9) were not significantly diminished compared with donor LVisolated mitochondria (n=7) for glycolysis (pyruvate + malate)-or FA (palmitoylcarnitine)-derived substrates, and mitochondrial densities, assessed via citrate synthase activity, were consistent between groups.Transmission electron microscopy images also showed no ultrastructural remodeling for failing vs. donor mitochondria; however, the fraction of lipid droplets (LDs) in direct contact with a mitochondrion was reduced, and the average distance between an LD and its nearest neighboring mitochondrionwas increased.Analysis ofFAprocessing gene expression between donor and failing LVs revealed 0.64-fold reduced transcript levels for the mitochondrial-LD tether, perilipin 5, in the failing myocardium (P = 0.003). Thus, reduced FA use in heart failure may result from improper delivery, potentially via decreased perilipin 5 expression and mitochondrial-LD tethering, and not from intrinsic mitochondrial dysfunction.-Holzem, K. M., Vinnakota, K. C., Ravikumar, V. K., Madden, E. J., Ewald, G. A., Dikranian, K., Beard, D. A., Efimov, I. R. Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts.
AB - During human heart failure, the balance of cardiac energy use switches from predominantly fatty acids (FAs) to glucose. We hypothesized that this substrate shift was the result of mitochondrial degeneration; therefore, we examined mitochondrial oxidation and ultrastructure in the failing human heart by using respirometry, transmission electron microscopy, and gene expression studies of demographically matched donor and failing human heart left ventricular (LV) tissues. Surprisingly, respiratory capacities for failing LV isolated mitochondria (n = 9) were not significantly diminished compared with donor LVisolated mitochondria (n=7) for glycolysis (pyruvate + malate)-or FA (palmitoylcarnitine)-derived substrates, and mitochondrial densities, assessed via citrate synthase activity, were consistent between groups.Transmission electron microscopy images also showed no ultrastructural remodeling for failing vs. donor mitochondria; however, the fraction of lipid droplets (LDs) in direct contact with a mitochondrion was reduced, and the average distance between an LD and its nearest neighboring mitochondrionwas increased.Analysis ofFAprocessing gene expression between donor and failing LVs revealed 0.64-fold reduced transcript levels for the mitochondrial-LD tether, perilipin 5, in the failing myocardium (P = 0.003). Thus, reduced FA use in heart failure may result from improper delivery, potentially via decreased perilipin 5 expression and mitochondrial-LD tethering, and not from intrinsic mitochondrial dysfunction.-Holzem, K. M., Vinnakota, K. C., Ravikumar, V. K., Madden, E. J., Ewald, G. A., Dikranian, K., Beard, D. A., Efimov, I. R. Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts.
KW - Electron microscopy
KW - Energy substrate
KW - Lipid droplet
KW - Oxidative respiration
KW - Perilipin 5
UR - http://www.scopus.com/inward/record.url?scp=84980318156&partnerID=8YFLogxK
U2 - 10.1096/fj.201500118R
DO - 10.1096/fj.201500118R
M3 - Article
C2 - 27075244
AN - SCOPUS:84980318156
SN - 0892-6638
VL - 30
SP - 2698
EP - 2707
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -