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

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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.