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Deuterated polyunsaturated fatty acids as protective therapy in the treatment of Barth syndrome

Deuterated polyunsaturated fatty acids as protective therapy in the treatment of Barth syndrome
Catherine F. Clarke, PhD, Professor and Chair, University of California at Los Angeles, Los Angeles, CA

Award—US $100,000 over 2-year period

*This grant is made possible by support from the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome


Recent research suggests that phospholipases and tafazzin acyl transferase (TAZ)1 work together to repair peroxidized fatty acyl chains of cardiolipin (CL). Thus, the same phospholipase and TAZ-mediated acylation activities responsible for remodeling newly synthesized CL into the mature tetralinoleoyl-CL (TLCL) also mediate the repair of peroxidized CL (CLOX). The susceptibility of TLCL to peroxidation has been appreciated for nearly 20 years, and a variety of antioxidant therapies that inhibit oxidative stress have been explored as treatments. However, reducing oxidative damage by boosting cellular repair systems and/or antioxidant levels is inefficient. This is particularly true for mitigating damage due to lipid peroxidation, a process that is initiated by a single radical species and amplified by chain reactions.

Mature or repaired TLCL contains four acyl chains derived from polyunsaturated fatty acids (PUFAs). PUFAs including linoleic (Lin, 18:2 n−6) are essential nutrients that are highly vulnerable to lipid peroxidation. The linoleoyl chains of CL are susceptible to peroxidation due to the presence of bis-allylic hydrogen atoms at the position between the double bonds. The hallmark chemistry of PUFA autoxidation is the facile abstraction of a bis-allylic hydrogen atom, resulting in the formation of a radical that, in the presence of oxygen, forms a lipid peroxyl radical that in turn elicits a chain reaction of lipid peroxidation, amplifying the initial oxidative insult. Here we propose to test the idea that CL can be synthesized in a fortified form where it is protected from lipid peroxidation. We suggest that supplementation of diets (or cell culture medium) with isotope reinforced polyunsaturated fatty acids (D-PUFAs) will result in the de novo synthesis of oxidation resistant CL and preserve mitochondria function. Replacement of just the 11,11 bis-allylic hydrogen atoms with deuterium atoms (11,11-D2-linoleic acid or D2-Lin), termed site-specific isotope reinforcement, profoundly inhibits PUFA peroxidation, protects against oxidative stress, preserves mitochondrial respiratory function and confers cell protection. Preservation of mitochondrial function is likely to constitute an important mechanism of cell protection against the oxidative stress conditions known to exist in Barth syndrome (BTHS) patients.

We propose to test the efficacy of D2-Lin supplementation in cellular models of Barth syndrome. Saccharomyces cerevisiae, baker’s yeast, is a superb model because yeast take up exogenously supplied PUFAs and incorporate them into membrane phospholipids, including CL. Yeast mutants with defects in CL synthesis (Δcrd1), or CL remodeling (Δcld1 or Δtaz1) will be compared to a parental isogenic wild-type strain. The yeast mutant and wild-type strains will be treated with Lin or D2-Lin, and we will investigate the effect of such treatment on CL isoforms, the status of CLOX, mitochondrial function and cell viability. We will also determine how Lin and D2-Lin treatments affect the biosynthesis of coenzyme Q (ubiquinone or CoQ). Like CL, CoQ is a membrane lipid essential for mitochondrial respiratory metabolism. CoQ also functions as a crucial lipid soluble antioxidant. Several lines of evidence suggest a close connection between CoQ and CL. Hence, it will be important to determine whether treatment with D2-Lin mitigate the effects of Δtaz1 on CoQ biosynthesis. We will next determine whether beneficial effects of D2-Lin treatment also show protective effects in human cell models of Barth syndrome. Lin is an essential fatty acid, and human cells also avidly take up and incorporate Lin (and D2-Lin) into membrane phospholipids. We will use a recently established genome-edited human BTHS cell culture model expressing a loss of function BTHS allele. Our studies will determine whether treatment with D2-Lin may ameliorate some of the mitochondrial defects in both yeast and human BTHS cell models, and may pave the way to test treatments with D2-Lin in BTHS patients.

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