Promotion of plasmalogen biosynthesis reverse lipid changes in a Barth Syndrome cell model

Bozelli JC, Lu D, Atilla-Gokcumen GE, and Epand RM. (2020) Promotion of plasmalogen biosynthesis reverse lipid changes in a Barth Syndrome cell model. Molecular and Cell Biology of Lipids, 1865(6).

Barth Syndrome (BTHS), a rare genetic disorder with a prevalence of less than 1 in 300 000, is caused by an X-linked recessive mutation in the tafazzin gene. Muscle weakness is characteristic of the rare syndrome, including a weakened enlarged heart that can be fatal in childhood or cause a shorter life expectancy in those that survive into adulthood. A loss-of-function of tafazzin results in a reduction in the mitochondria-specific lipid, cardiolipin, which is important in mitochondrial structure and function. Interestingly, a reduction in plasmalogens has also been described in tafazzin knockdown mice and BTHS patients. In this study, lymphoblasts were derived from BTHS patients and displayed characteristics of the syndrome including a reduced level of plasmalogens when compared to the control lymphoblasts. BTHS lymphoblasts and control lymphoblasts were evaluated to determine if plasmalogen precursors could normalize cell viability, mitochondrial biogenesis, and mitochondrial membrane potential.

To increase plasmalogen biosynthesis, the lymphoblasts were treated with an alkyl glycerol plasmalogen precursor, 1-O-hexadecylglycerol (HG), and ethanolamine. Ethanolamine plasmalogen levels were increased 100% compared to untreated BTHS lymphoblasts and were 60% greater than plasmalogen levels in control lymphoblasts. To study the effects of plasmalogen precursor treatment on cell viability, cellular adenosine triphosphate (ATP) was measured to assess cell proliferation and toxicity. Without treatment, BTHS lymphoblasts had 2.3-fold higher cellular ATP compared to controls; indicating these cells are compensating for disrupted mitochondrial function. Plasmalogen precursor treatment did not influence cell viability, as determined through unchanged ATP levels with treatment. However, treatment did reduce the number of mitochondria. Untreated BTHS cells had mitochondria levels as high as 4-fold greater than control lymphoblasts, but when treated, were lowered to only 2-fold greater than the controls. Mitochondrial membrane potential was also normalized after the plasmalogen precursor treatment, indicating that electron transport was more efficient, and this could account for the reduction in the number of mitochondria. Following plasmalogen treatment, fewer mitochondria would have been required to provide the same level of energy output as that produced by the increased number of mitochondria in untreated BTHS lymphoblasts.

Bozelli et al provide evidence for the importance of plasmalogens in BTHS, specifically on mitochondrial biogenesis and function, and demonstrate the potential benefit of supplying plasmalogen precursors to patients with BTHS. A key role of plasmalogens is in membrane structure and fluidity, as the double membrane of mitochondria is where many biochemical functions such as respiration and energy production occur. The findings suggest an important role for plasmalogens in the structure and proper function of mitochondria and that other disorders characterized by plasmalogen deficiency, including rhizomelic chondrodysplasia punctata (RCDP), could be impacted by mitochondrial dysfunction. Further research looking at mitochondria in plasmalogen deficiencies could provide insight into how this deficiency results in the observed clinical manifestations in these disorders.