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MITOchondrial therapy to increase cardiac FORCE and enhance exercise performance


The heart is the engine of life; an unremitting muscular pump that continuously circulates blood throughout the body to supply other organs with the energy to thrive. The heart depends on a continuous supply of energy in the form of ATP, which is produced in mitochondria, the energy factories of the cell. Mitochondria are unique multifunctional organelles which, in addition to energy production, regulate cardiac calcium handling, redox balance, cellular growth and cell death.


In patients with heart failure (HF) severe defects in mitochondria occur that cause mitochondrial oxidative stress, alter cardiac calcium handling,  compromise ATP production and promote cardiomyocyte apoptosis. Cardiac ATP production falls short and the heart becomes unable to pump enough blood to meet the body’s energy demands. The failing heart is often compared with an “engine out of fuel”. The mechanisms responsible for mitochondrial dysfunction in heart failure are poorly understood and specific therapies are lacking.


We believe that MITOchondrial dysfunction offers an unique opportunity for target for therapy to restore the FORCE of the failing heart.  In the MITO-FORCE project we aim to discover new therapeutic targets and develop new pharmacological interventions to restore mitochondrial function in heart failure.

Finding the cause of mitochondrial dysfunction in heart failure

We recently discovered mitochondrial reprogramming as a key mediator of mitochondrial dysfunction and heart failure development. We aim to identify and explore key transcriptional events that cause mitochondrial dysfunction in heart failure, using an omics approach (transcriptomics, metabolomics, proteomics). We have been able to identify several potential targets for therapy and are currently validating these targets in transgenic models systems. Our most recent work uncovered a crucial role for the mitochondrial protein ATPase inhibitory factor 1 in cardiac calcium handling an pathological cardiac growth.


Mitochondrial contributions  to muscle growth in health and disease

Physiological stimuli such as exercise or pregnancy activate a coordinated physiological growth response where a proportionate increase in cardiomyocyte volume and mitochondrial density result in improvements in exercise performance. In response to pathological stressors such as hypertension or valve disease, the coordination is lost and mitochondrial growth is compromised. In this part of MITO-FORCE we aim to identify pathways responsible for physiological mitochondrial adaptations to exercise. We believe that improved understanding of the normal mitochondrial adaptations to exercise could lead to new strategies to treat or prevent mitochondrial dysfunction in HF. Recent work identified A-kinase interacting protein as a critical regulator of cardiac and mitochondrial growth in response to exercise.


Mitochondrial interventions

Mechanistic insights obtained from the strategies above are translated into pharmacological interventions that are tested in established animal models and proof of concept clinical trials. We recently discovered that Sodium Glucose Co-Transporter inhibitors improve cardiac function by reprogramming cardiac metabolism towards increased ketone oxidation. In addition, we discovered that oral ketone administration improves cardiac function. These insights are currently tested in the Ketone-HF project.

People involved

International collaborations

  • John Walker, Cambridge University, Cambridge, UK
  • Gerald Dorn, University of Washington St. Lois, St. Lois, USA
  • Joan Brown, University of California San Diego, San Diego, USA
  • Daniel Kelly, University of Pennsylvania, Philadelphia, USA