Many of the manifestations of some long chain fatty acid oxidation disorders (LCFAOD), including trifunctional protein (TFP) deficiency and long chain 3-hydroxy-acyl-CoA dehydrogenase (LHAD) deficiency, may be caused by errors in cardiolipin production.

This is according to new results that were presented at the International Network for Fatty Acid Oxidation Research and Management (INFORM) annual meeting by Eduardo Vieira Neto, MD, PhD, from the Division of Medical Genetics and Genomics, Department of Pediatrics, at the University of Pittsburgh School of Medicine in Pennsylvania.

TFP and LCHAD deficiencies are caused by mutations in either the HADHA or HADHB genes that lead to errors in the production of the TFP protein α and/or β subunits. The α subunit of the TFP protein also contains a region called monolysocardiolipin acyltransferase (MLCLAT-1) which is responsible, along with the protein tafazzin, for the correct remodeling of cardiolipin.

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Cardiolipin (diphosphatidylglycerol) is an integral part of the internal mitochondrial membrane and its cone-like shape helps to form the cristae. It also helps to form the membrane supercomplexes (respirasomes) containing complexes 1, 3, 4, and cytochrome C, which is necessary for the electron transport chain.

In the study presented by Dr. Neto, 5 cell lines taken from patients with either TFP deficiency (n=4) or LCHAD deficiency (n=1) were compared to 3 healthy control patient cell lines collected from fibroblasts.

Two of the patients with TFP deficiency had mutations in the HADHA gene while the other 2 had mutations in the HADHB gene. The patient with LCHAD deficiency had a p.E510Q mutation in the HADHA gene.

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Analysis of the cells showed that all 5 of the patient cell lines had lower levels of cardiolipin compared to the healthy controls (P =.0095). In 3 of the 5 patient cell lines, the levels of monolyso-cardiolipins were higher than the controls, while the other 2 were similar. However, the disease group was higher than controls on average (P =.0416).

Another rare disorder called Barth syndrome has elevated ratios of monolyso-cardiolipins versus cardiolipins as well. Barth syndrome is caused by mutations in the tafazzin protein, resulting in cardiolipin remodeling errors. 

“These results suggest a disruption in [cardiolipin] reacylation in TFP/LCHAD deficiency, similar to Barth syndrome, and point to a possible function of MLCLAT-1 as a CL remodeling enzyme,” Dr. Neto said. “This finding offers new potential targets for development of drug therapy.”

One such therapy mentioned in the presentation was elamipretide (SS-31), which selectively binds to cardiolipin and can help stabilize the molecules. “This could be useful in several diseases where cardiolipin is unstable or is oxidized by reactive oxygen species or its remodeling is affected,” Dr. Neto added.


Cardiolipin metabolism in TFP/LCHAD deficiency. Presented at: International Network for Fatty Acid Oxidation Research and Management (INFORM) Annual Meeting: October 28, 2021; Virtual.