Lipid News

Targeting cardiolipin modification in a genetic disorder

Arianna F. Anzmann Olivia Sniezek Hilary Vernon
By Arianna F. Anzmann, Olivia Sniezek and Hilary Vernon
Nov. 2, 2021

Barth syndrome, an X-linked disorder that primarily affects males, is characterized by weak skeletal muscles, cardiomyopathy and low neutrophils (the white blood cells that fight bacteria), among other medical concerns. The symptoms can be treated, but no disease-specific therapies have been approved. This rare and serious lipid metabolism disorder is caused by pathogenic variants in the gene TAFAZZIN.

Barth-Syndrome-890x1061.jpg
Arianna Anzmann
Targeting cardiolipin in TAFAZZIN deficiency has shown promise in improving cellular defects in an HEK293 model of TAFAZZIN deficiency and clinical problems seen in Barth syndrome, including cardiac and skeletal muscle dysfunction.

TAFAZZIN encodes for an enzyme involved in the final remodeling step of cardiolipin, a key phospholipid localized to the mitochondrial inner membrane. TAFAZZIN deficiency results in abnormal mitochondrial cardiolipin quantity and composition and subsequent mitochondrial dysfunction. Whereas researchers have known the primary biochemical defect in Barth syndrome for several decades, two important questions have remained unanswered: What molecular pathways are impacted by TAFAZZIN deficiency and contribute to resultant mitochondrial dysfunction? And why does deficiency of an enzyme that affects a molecule present in every cell in the body affect such a specific set of tissues? Answering these questions is key to developing treatments for Barth syndrome.

Combined proteomic, metabolomic and functional studies in a CRISPR-edited TAFAZZIN knockout HEK293 cell model recently have offered insight into these questions. Among the molecular abnormalities that researchers at the Johns Hopkins School of Medicine identified in this cellular model were defects in the expression, assembly and function of complex I of the mitochondrial respiratory chain. The researchers also found increased expression of presenilin-associated rhomboidlike protein, a protease localized to the inner mitochondrial membrane, and abnormal cleavage of its downstream target, phosphoglycerate mutase 5. Thus, TAFAZZIN deficiency affects mitochondrial respiratory chain function and quality control.

The researchers found that both elamipretide, a molecule that binds to cardiolipin, and bromoenol lactone, which inhibits nascent cardiolipin deacylation, partially remediate these mitochondrial defects. Determining if these pathways are differentially impacted in spared versus affected tissues may help researchers understand what causes the pleiotropic effects of TAFAZZIN deficiency and suggest therapeutic approaches.

In addition to demonstrating the effects of cardiolipin targeting in cellular models of TAFAZZIN deficiency in the lab, this approach has shown clinical promise. In a recent study published in the journal Genetics in Medicine, clinical researchers at the Johns Hopkins School of Medicine described results of a placebo-controlled, crossover clinical trial to investigate the role of elamipretide in 12 patients affected by Barth syndrome. The study participants showed improvement in multiple clinical parameters, including muscle strength, exercise tolerance and cardiac stroke volume, after 48 weeks of treatment.

Together, these studies show the translational potential of cellular disease modeling and pathway targeting in lipid metabolism disorders.

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Arianna F. Anzmann
Arianna F. Anzmann

Arianna Anzmann is a review analyst at GeneDx and a graduate of the human genetics doctoral program at the John’s Hopkins School of Medicine.

Olivia Sniezek
Olivia Sniezek

Olivia Sniezek is a graduate student in the predoctoral training program in human genetics at the John’s Hopkins School of Medicine.

Hilary Vernon
Hilary Vernon

Hilary Vernon is an associate professor of genetic medicine at Johns Hopkins University.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Is there a mystery in the monkeypox antiviral?
News

Is there a mystery in the monkeypox antiviral?

May 24, 2022

As monkeypox becomes an international concern, interest grows in tecovirimat; this smallpox drug targets a structural protein that helps wrap the virus in a second lipid bilayer.

Researchers investigate self-regulation of an enzyme with critical cellular functions
News

Researchers investigate self-regulation of an enzyme with critical cellular functions

May 24, 2022

They found that one mechanism of CK1 activity, and thus one mechanism of regulation, is the self-phosphorylation of a conserved amino acid residue in its catalytic domain.

What is monkeypox?
Science Communication

What is monkeypox?

May 23, 2022

A microbiologist explains what’s known about this smallpox cousin.

A simple method to determine phase preference of proteins on live cell membranes
Journal News

A simple method to determine phase preference of proteins on live cell membranes

May 22, 2022

“The phase preference of molecules used to be difficult and time-consuming to establish. This new method, detected by chance, provides results in at most 15 minutes on live cells,” Thorsten Wohland said.

Study of Alzheimer’s marker prompts warning about serine supplements
News

Study of Alzheimer’s marker prompts warning about serine supplements

May 20, 2022

They have been advertised to improve memory and cognitive function.

Why is the 100-year-old BCG vaccine so broadly protective in newborns?
News

Why is the 100-year-old BCG vaccine so broadly protective in newborns?

May 19, 2022

Study finds changes in metabolite and lipid profiles, providing clues for designing future vaccines for newborns.