New Study Deepens Link Between Heart Failure and Mitochondrial Health
The heart is a hard-working muscle. Each day it beats approximately 100,000 times without any breaks. It’s been estimated that over the course of an average lifetime, the human heart will beat more than 2.5 billion times.
Each of those heartbeats uses energy. Cellular energy is consumed when the heart muscle contracts, and energy is even used to help the heart muscle relax and reset. As the body’s demand for blood changes, the heart can adjust its workload to keep pace. For example, during exercise the heart’s output can more than triple to deliver nutrients and oxygen to active muscles.
But sometimes unwanted changes send the heart into more permanent overdrive. When faced with a blocked artery, for example, the heart starts pumping harder to deliver the same amount of blood to the body. As the heart adapts to this increased workload, it can grow larger--a phenomenon called hypertrophy--and increase cellular energy production to keep up the pace.
The Connection Between Oxidative Stress and Heart Failure
Heart cells depend on healthy mitochondria to constantly generate the energy they need. But mitochondria aren’t perfect. As they generate cellular energy, mitochondria also contribute to a type of cellular stress called “oxidative stress” by producing reactive oxygen species, or ROS. When energy production kicks into high gear, ROS production also increases and leads to higher levels of oxidative stress [1].
As their name suggests, ROS are highly reactive meaning that they readily interact with cellular molecules such as fats, proteins, and DNA. These interactions alter the chemical composition of the molecules, which can in turn change their function. As a result, increased levels of oxidative stress can lead to mitochondrial damage as ROS slowly chip away at their molecular components.
Mitochondria damaged by oxidative stress become less efficient at generating cellular energy. And less efficient mitochondria tend to produce higher quantities of ROS, precipitating a vicious cycle of damage and decline. This decline in mitochondrial efficiency, often called mitochondrial dysfunction, is also a central feature of heart failure [2].
Boosting NAD to Support Stressed Mitochondria
The critical link between mitochondrial dysfunction and heart failure has led scientists to look for strategies to treat heart failure by improving mitochondrial health. Previous research has shown that nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) can boost NAD to improve mitochondrial and cardiac function in mouse models of heart failure [3-10]. Multiple clinical trials have already been registered to try to translate these promising preclinical findings to human heart failure patients.
Now, a team of researchers led by Professor Ajay Shah and Dr. Ioannis Smyrnias from King’s College London - British Heart Foundation Centre of Excellence have deepened our understanding of NAD and heart failure [11]. Published in the Journal of the American College of Cardiology, the preclinical study sheds new light on the cellular mechanism by which NR improves mitochondrial function to keep an overworked heart beating.
New Insight Into How NR Helps Counteract Mitochondrial Damage
In the new study, Prof. Shah and his team tested the effects of NR in both isolated rat heart cells and mouse models of heart failure. In both systems, NR helped improve mitochondrial function in the face of stress. In the heart failure model, NR supplementation also reduced the number of apoptotic (i.e., dead) heart cells and helped maintain the heart’s ability to pump blood throughout the body.
Notably, the researchers found that NR improved mitochondrial function in heart cells by stimulating one of the cell’s natural mitochondrial repair mechanisms. This mechanism, called the mitochondrial unfolded protein response (UPRmt), helps mitochondria stay strong in the face of oxidative stress. When the researchers manipulated cells to prevent the UPRmt from functioning properly, the beneficial effects of NR also went away.
Molecular Tune-Ups Keep Mitochondria Up and Running
The energy-generating machinery inside mitochondria is made up of proteins. These proteins must be properly folded to function properly. Different kinds of stresses from overloaded mitochondria can damage proteins, causing them to fold incorrectly and lose function. The UPRmt is activated when misfolded proteins accumulate inside mitochondria. It gives the mitochondria a “molecular tune-up” by salvaging misfolded proteins and clearing out those that are beyond repair.
Other researchers have already shown that NR stimulates the UPRmt, particularly under conditions of age and metabolic stress. In 2013, scientists first demonstrated NR’s ability to stimulate the UPRmt in worms and isolated mammalian liver cells [12]. In mammalian cells, NR’s effect depended on the activity of the sirtuin SIRT1. In 2016, two new mouse studies developed this work, showing that oral NR supplementation activates the UPRmt in the muscle stem cells of aged mice and in the liver cells of mice fed a high fat high sugar diet [13-14].
Together, these studies have led scientists to propose the working model that NR increases NAD levels, which in turn activates NAD-consuming sirtuins. These sirtuins then turn on a suite of pathways to promote mitochondrial growth and repair, including the UPRmt.
Targeting the UPRmt Could Be Good News for Heart Failure Patients
To begin to translate their findings to humans, Prof. Shah and colleagues collected heart tissue and blood samples from aortic stenosis patients undergoing a heart valve replacement surgery. Although these patients all had stressed hearts, they did not all have the same level of UPRmt activation. This natural variation allowed the researchers to test for correlations between UPRmt activity and a variety of measures associated with heart health.
Across patients, higher levels of UPRmt activity correlated with reduced numbers of apoptotic/dying heart cells; healthier, less fibrotic heart tissue; and lower levels of circulating blood markers associated with heart failure.
“This study suggests that cardiac pathology causes the misfolding of mitochondrial proteins, which activates adaptive aspects of the UPRmt, and that by minimizing the misfolding of mitochondrial proteins, enhancing the UPRmt might serve as a potential therapeutic strategy for treating heart disease,” wrote Dr. Christopher Glembotski and colleagues from the San Diego State Heart Institute in an editorial comment on the study [15].
Follow-up work is still needed to understand whether NR affects any of these outcomes. But this latest study provides preliminary evidence that strategies to boost the UPRmt to improve mitochondrial function have the potential to improve heart health in people.
References
Cui, H., Y. Kong, and H. Zhang, Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct, 2012. 2012: p. 646354.
Rosca, M.G. and C.L. Hoppel, Mitochondrial dysfunction in heart failure. Heart Fail Rev, 2013. 18(5): p. 607-22.
Xu, W., et al., Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart. Cell Rep, 2015. 13(3): p. 533-545.
Diguet, N., et al., Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation, 2017.
Vignier, N., et al., Rescue of biosynthesis of nicotinamide adenine dinucleotide (NAD+) protects the heart in cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet, 2018.
Yamamoto, T., et al., Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One, 2014. 9(6): p. e98972.
Martin, A.S., et al., Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. JCI Insight, 2017. 2(14).
Zhang, R., et al., Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. J Mol Cell Cardiol, 2017. 112: p. 64-73.
Lee, C.F., et al., Normalization of NAD+ Redox Balance as a Therapy for Heart Failure. Circulation, 2016. 134(12): p. 883-94.
Nadtochiy, S.M., et al., Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH. J Mol Cell Cardiol, 2018.
Smyrnias, I., et al., Cardioprotective Effect of the Mitochondrial Unfolded Response During Chronic Pressure Overload. J Am Coll Cardio, 2019. 73(14).
Mouchiroud, L., et al., The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell, 2013. 154(2): p. 430-41.
Zhang, H., et al., NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 2016. 352(6292): p. 1436-43.
Gariani, K., et al., Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology, 2016. 63(4): p. 1190-204.
Glembotski, C.C., et al., Unfolding the Roles of MItochondria as Therapeutic Targets for Heart Disease. J Am Coll Cardio, 2019. 73(14).