How a rare genetic disorder affects mitochondrial fatty acid synthesis and causes neurodegeneration

A new study published in the journal Nature Metabolism has shed light on the molecular mechanism behind a rare genetic disorder that causes progressive neurological problems in children. The disorder, known as mitochondrial enoyl reductase protein-associated neurodegeneration (MEPAN) syndrome, is caused by mutations in the MECR gene that encodes an enzyme involved in mitochondrial fatty acid synthesis. The researchers found that the mutations disrupt the balance of fatty acids and other metabolites in the mitochondria, leading to excessive accumulation of ceramide and defective iron metabolism. These metabolic abnormalities trigger neuronal death and neurodegeneration in patients and animal models of MEPAN syndrome.

MEPAN syndrome: a rare and devastating condition

MEPAN syndrome is a rare inherited disorder that affects the nervous system. It was first described in 2016 by a team of researchers led by Dr. Hugo J. Bellen, distinguished service professor at Baylor College of Medicine, and Chair of Neurogenetics at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital (Duncan NRI). The researchers identified mutations in the MECR gene as the cause of MEPAN syndrome in six patients from four families.

How a rare genetic disorder affects mitochondrial fatty acid synthesis and causes neurodegeneration
How a rare genetic disorder affects mitochondrial fatty acid synthesis and causes neurodegeneration

The MECR gene encodes an enzyme called mitochondrial enoyl coA-reductase, which catalyzes the last step in mitochondrial fatty acid synthesis. Fatty acids are essential components of complex lipids that are involved in various cellular functions, such as energy production, membrane structure, and signaling. Most fatty acids are synthesized in the cytoplasm, but a small fraction are also synthesized in the mitochondria, which are the organelles that generate energy for the cells.

Patients with MEPAN syndrome typically develop symptoms in early childhood, such as dystonia (involuntary muscle contractions), ataxia (loss of coordination), speech problems, and vision loss. The disease progresses over time and leads to severe disability and blindness. There is no cure or specific treatment for MEPAN syndrome.

How MECR mutations affect mitochondrial metabolism and neurodegeneration

To understand how MECR mutations cause MEPAN syndrome, Dr. Bellen and his colleagues used CRISPR technology to delete the MECR gene in fruit flies and mice, which are commonly used as animal models for studying human diseases. They also analyzed fibroblast cells from MEPAN patients and compared them with healthy controls.

They found that MECR mutations impair mitochondrial fatty acid synthesis and alter the levels of various metabolites in the mitochondria. In particular, they observed that MECR mutations cause an accumulation of ceramide, a type of lipid that regulates cell death, inflammation, and stress responses. Ceramide accumulation was associated with increased oxidative stress, mitochondrial dysfunction, and neuronal death in the animal models and patient cells.

The researchers also discovered that MECR mutations affect iron metabolism in the mitochondria. Iron is an essential element for many biochemical reactions, but excess iron can be toxic and cause oxidative damage to DNA, proteins, and lipids. The researchers found that MECR mutations reduce the expression of genes involved in iron transport and storage, leading to iron deficiency in some tissues and iron overload in others. Iron imbalance was also linked to neuronal death and neurodegeneration in the animal models and patient cells.

Implications for diagnosis and treatment of MEPAN syndrome

The study provides novel insights into the pathogenic mechanism of MEPAN syndrome and reveals a connection between mitochondrial fatty acid synthesis, ceramide metabolism, iron homeostasis, and neurodegeneration. The researchers suggest that measuring ceramide levels and iron status in blood or cerebrospinal fluid could be useful biomarkers for diagnosing MEPAN syndrome and monitoring its progression.

The study also opens new avenues for developing potential therapies for MEPAN syndrome by targeting ceramide or iron metabolism. For example, drugs that inhibit ceramide synthesis or reduce ceramide levels could protect neurons from death and neurodegeneration. Similarly, drugs that modulate iron transport or chelate excess iron could prevent oxidative damage and restore mitochondrial function.

The researchers hope that their findings will not only benefit patients with MEPAN syndrome but also shed light on other neurodegenerative diseases that share common features, such as mitochondrial dysfunction, lipid dysregulation, iron imbalance, and neuronal loss.

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