The underlying molecular mechanisms for heart failure (HF) are multifactorial, with energy
dysregulation and oxidative stress appearing to be the key causes. The well-balanced energy
consumption/generation of the working heart is thought to be achieved by Ca2+ entry via
mitochondrial Ca2+ uniporter (MCU) which stimulates enzymes in the tricarboxylic acid (TCA)
cycle for ATP generation, referred to as excitation-bioenergetics (EB) coupling. Surprisingly,
knockout of MCU in the heart results in minimal defects in bioenergetics, suggesting that other
Ca2+ transporters also may participate in EB coupling. We have previously shown that ryanodine
receptor type 1 (RyR1) is expressed in cardiac mitochondria (mRyR1), playing a key role in EB
coupling. Several groups have confirmed our findings, including recent reports showing that Ca2+
release from the sarcoplasmic reticulum (SR) is tunneled to mRyR to stimulate ATP production.
We have also obtained new data showing that RyR1 expression is increased in mouse and human
hypertrophied heart. The mitochondria isolated from RyR1 over expression (OE) mouse hearts
have higher Ca2+ concentrations ([Ca2+]m) and increased ROS generation. This RyR1 OE mouse
also shows cardiac hypertrophy and higher frequency of Ca2+ sparks, suggesting leakier RyR2
for Ca2+. Taken together, we propose a novel central hypothesis: Hypertrophic stimuli lead to
mRyR1 overexpression in heart to compensate for increased energy demands by promoting
mitochondrial Ca2+ uptake for EB coupling (Aim 1). However, chronic increases in mitochondrial
Ca2+ uptake causes a sustained high level of ROS generation via Rieske iron-sulfur protein (RISP)
at complex III (Aim 2). The increased ROS would oxidize and thus activate nearby SR RyR2
further increase mitochondrial Ca2+ loading due to constant Ca2+ leak from SR. This vicious cycle
of ¿mRyR1¿¿[Ca2+]m¿¿ROS¿¿SR RyR2 Ca2+ leak¿¿[Ca2+]m (¿: leads to, ¿: increases), which
causes mitochondrial dysfunction including opening of mitochondrial permeability transition pore.
Consequently, the heart is failing because of the inadequate energy for pumping and higher
myocyte death and injury (Aim 3). The successful research outcome from this proposal will
provide a new paradigm for HF: that RyR1 OE in the stressed heart is an initial adaptive
mechanism that sequentially become mal-adaptive, which subsequently leads to HF. This new
information will highlight a potentially innovative therapeutic strategy for development of novel
inhibitors that are more selective for RyR1 than for RyR2 – such as dantrolene which has already
been frequently used for treating malignant hyperthermia patients – as effective treatments of
cardiac hypertrophy and HF.
