Mitochondrial Protein in Cardiac Muscle Cells Linked to Heart Failure, Study Finds

Reducing a protein found in the mitochondria of cardiac muscle cells initiates cardiac dysfunction and heart failure, a finding that could provide insight for new treatments for cardiovascular diseases, a study led by Georgia State University has shown.

The researchers discovered that reducing an outer mitochondrial membrane protein, FUN14 domain containing 1 (FUNDC1), in cardiac muscle cells, also known as cardiomyocytes, activates and worsens cardiac dysfunction. Also, disrupting how FUNDC1 binds to a particular receptor inhibited the release of calcium from another cell structure, the endoplasmic reticulum (ER), into the mitochondria of these cells and resulted in mitochondrial dysfunction, cardiac dysfunction and heart failure. The findings are published in the journal Circulation.

Mitochondria play numerous roles in the body, including energy production, reactive oxygen species generation and signal transduction. Because the myocardium, the muscular wall of the heart, is a high-energy-demand tissue, mitochondria play a central role in maintaining optimal cardiac performance. Growing evidence suggests deregulated mitochondrial activity plays a causative role in cardiovascular diseases.

In the body, mitochondria and ER are interconnected and form their own endomembrane networks. The points where mitochondria and ER make physical contact and communicate are known as mitochondria-associated ER membranes (MAMs). MAMs play a major role in regulating the transfer of calcium between ER and mitochondria. Dysfunctional MAMs are involved in several neuronal disorders, including Alzheimer’s disease and Parkinson’s disease. Until now, the role of MAMs in cardiac pathologies has not been well understood.

“Our study found the formation of MAMs mediated by the mitochondrial membrane protein FUNDC1 was significantly suppressed in patients with heart failure, which provides evidence that FUNDC1 and MAMs actively participate in the development of heart failure,” said Dr. Ming-Hui Zou, director of the Center for Molecular and Translational Medicine at Georgia State and a Georgia Research Alliance Eminent Scholar in Molecular Medicine. “This work has important clinical implications and provides support that restoring proper function of MAMs may be a novel target for treating heart failure.”

The researchers used mouse neonatal cardiomyocytes, mice with a genetic deletion of the FUNDC1 gene, control mice with no genetic deficiencies and the cardiac tissues of patients with heart failure.

The cardiac functions of the mice were monitored using echocardiography at 10 weeks of age. Mice with the genetic deletion of FUNDC1 had markedly reduced ventricular filling velocities, prolonged left ventricular isovolumic relaxation time, diastolic dysfunction, decreased cardiac output (which indicates impaired systolic functions) and interstitial fibrosis of the myocardium, among other issues. The mitochondria in the hearts of mice with FUNDC1 gene deletion were larger and more elongated, a 2.5-fold increase of size compared to mitochondria in the control mice.

To determine if FUNDC1 reduction occurred in human hearts and contributed to heart failure in patients, the researchers examined four heart specimens from heart failure patients and four heart specimens from control donors. They found the levels of FUNDC1 were significantly reduced in patients with heart failure compared to control donors. Also, the contact between ER and mitochondria in failed hearts was significantly reduced. In addition, the mitochondria in heart failure hearts were more elongated compared to those in control donors.

Study Discovers Potential New Target For Treatment Of Spinal Muscular Atrophy

For the first time, scientists found that in spinal muscular atrophy (SMA), the affected nerve cells that control muscle movement, or motor neurons, have defects in their mitochondria, which generate energy used by the cell. Impaired mitochondrial function and structure in motor neurons were discovered before symptoms occurred, suggesting a role in disease development.

These findings, published inHuman Molecular Genetics, point to new possibilities for targeted therapy for SMA.

“Restoring mitochondrial function might be a new treatment strategy for SMA,” said Yongchao Ma, PhD, senior author and Ann Marie and Francis Klocke, MD Research Scholar, Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago. He also is Assistant Professor of Pediatrics, Neurology and Physiology at Northwestern University Feinberg School of Medicine.
Infants born with SMA are not able to hold up their heads or sit up on their own, and they rarely survive beyond 2 years of age.

“While the genetic cause of this devastating disease has been identified, our study describes how mitochondrial dysfunction might contribute to motor neuron destruction even before the onset of symptoms,” said Ma. “Our findings provide new insights into SMA pathogenesis, which is crucial to developing new therapies.”

Ma and colleagues first discovered that mitochondria was involved in SMA when they analyzed gene expression profiles of motor neurons from SMA and control mice. They observed that the genes related to many mitochondrial functions were significantly dysregulated in SMA motor neurons.

“This discovery was unexpected and led us to test whether mitochondrial functions were changed in motor neurons from SMA mouse models,” said Ma.

Using sophisticated technology, the study found that mitochondria in SMA motor neurons produce energy at a slower rate, depleting the nerve. SMA mitochondria was less healthy, as evidenced by its decreased membrane potential. It also had increased oxidative stress level, which is toxic to the neuron. The movement of mitochondria was impaired as well, which would cause it to get stuck at the junction between nerve and muscle, leaking toxins and eventually disrupting the connection. Mitochondria in SMA motor neurons was also fragmented and swollen, which is consistent with the functional defects measured by the study.

“Motor neurons have high energy demands, which would make them highly sensitive to defects in their mitochondria,” says Ma. “These defects might lead to the symptom of motor neuron degeneration in SMA,” says Ma.

Get a clue: Biochemist studies fruit fly to understand Parkinson’s disease, muscle wasting

The fruit fly may help us be less clueless about human muscle development and Parkinson’s disease.

Erika Geisbrecht, Kansas State University associate professor of biochemistry and molecular biophysics, is studying the fruit fly, or Drosophila melanogaster, to understand a gene called clueless, or clu. Geisbrecht and her research team have found a connection between clu and genes that cause Parkinson’s disease.

Geisbrecht’s team is among the first to focus on the connection between clu and mitochondrial function in fruit fly muscle cells. The researchers recently published their work in the journal Human Molecular Genetics.

“We are trying to understand how muscles develop and how healthy muscles are maintained throughout the entire life of a fruit fly in the hopes of applying this knowledge to the human body,” Geisbrecht said.

Geisbrecht uses fruit fly muscles as a model for human muscles because of their similar structures — approximately 85 percent of the human disease genes have corresponding genes in the fruit fly. Fruit flies also have a short lifecycle of 10 days from when the egg is laid to when adults emerge, which allows for the rapid observation of muscle development and maintenance.

The connection between fruit fly and human muscles has made it possible to understand the role of the clu gene that — when mutated — causes defects in the localization and turnover of damaged mitochondria. A buildup of damaged mitochondria ultimately affects the ability of muscles and nerves to function properly. Geisbrecht and her team are just beginning to understand how clu interacts with a gene called parkin that — when mutated in humans — results in Parkinson’s disease.

People who are born with mutations in the parkin gene do not develop Parkinson’s disease until later in adult life. The same is true for fruit flies with defects in clu or parkin: These fruit flies proceed through the larval and pupal stage of insect development and emerge as adults, but quickly die because their muscles and neurons degenerate.

“If you think about a tissue in the body that uses more energy than anything else, of course it’s your muscle tissue,” Geisbrecht said. “Proper mitochondrial function is essential to having healthy, developed muscles. It’s an important connection.”

Geisbrecht’s team plans to continue studying fruit flies to better understand the connection between human disease genes and muscle function. Their work could lead to better treatment for Parkinson’s disease or other muscle diseases.

Aside from muscle or neurodegenerative diseases, maintaining healthy muscle tissue also is important in the general population, where common diseases can also lead to muscle problems. For example, muscle wasting, or muscle deterioration, can be a huge problem for people with diabetes or cancer.

“Muscle wasting for people with end-stage diabetes or cancer is often a bigger problem than the cancer or diabetes itself because it causes people to become immobile and lose the ability to make their muscles function well again,” Geisbrecht said. “We want to understand what happens at the cellular level — what these genes or proteins are doing.”