2015 PNAS HF Santulli (First and Corresponding Author).pdf (3.57 MB)

2015 PNAS HF Santulli (First and Corresponding Author).pdf

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posted on 09.04.2018, 14:30 by Gaetano Santulli, Wenjun Xie, Steven R. Reiken, Andrew R.Marks
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Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial

for excitation–contraction (E–C) coupling. Mitochondria, the major

source of energy, in the form of ATP, required for cardiac contractility,

are closely interconnected with the SR, and Ca2+ is essential for optimal

function of these organelles. However, Ca2+ accumulation can

impair mitochondrial function, leading to reduced ATP production

and increased release of reactive oxygen species (ROS). Oxidative

stress contributes to heart failure (HF), but whether mitochondrial

Ca2+ plays a mechanistic role in HF remains unresolved. Here, we

show for the first time, to our knowledge, that diastolic SR Ca2+

leak causes mitochondrial Ca2+ overload and dysfunction in a murine

model of postmyocardial infarction HF. There are two forms of Ca2+

release channels on cardiac SR: type 2 ryanodine receptors (RyR2s)

and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine

models harboring RyR2 mutations that either cause or inhibit SR

Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial

Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiacspecific

deletion of IP3R2 had no major effect on mitochondrial fitness

in HF. Moreover, genetic enhancement of mitochondrial antioxidant

activity improved mitochondrial function and reduced posttranslational

modifications of RyR2 macromolecular complex. Our data demonstrate

that leaky RyR2, but not IP3R2, channels cause mitochondrial

Ca2+ overload and dysfunction in HF.


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