Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency
Eduardo Vieira Neto, Meicheng Wang, Austin J. Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van’t Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H. El-Gharbawy, Tamil S. Anthonymuthu, Yulia Y. Tyurina, Vladimir A. Tyurin, Valerian Kagan, Hülya Bayır, Jerry Vockley
Eduardo Vieira Neto, Meicheng Wang, Austin J. Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van’t Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H. El-Gharbawy, Tamil S. Anthonymuthu, Yulia Y. Tyurina, Vladimir A. Tyurin, Valerian Kagan, Hülya Bayır, Jerry Vockley
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Research Article Genetics Metabolism

Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency

Abstract

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.

Authors

Eduardo Vieira Neto, Meicheng Wang, Austin J. Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van’t Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H. El-Gharbawy, Tamil S. Anthonymuthu, Yulia Y. Tyurina, Vladimir A. Tyurin, Valerian Kagan, Hülya Bayır, Jerry Vockley

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Figure 2

Solid ribbon model of the missense mutation sites in the tetramer structure of the mitochondrial TFP.

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Solid ribbon model of the missense mutation sites in the tetramer struct...
(A) Mutations are identified in orange, α subunits in cream, and β subunits in yellow. Close-up views of the interaction of residues in wild-type (B, C upper panels), HADHA mutants (B bottom panels), and HADHB mutants (C bottom panels). All critical residues are shown as ball and stick, whereas the backbone is shown in cream color cartoon representation; numbering refers to reference sequences retrieved from National Center for Biotechnology Information (NCBI) (73, 74). Catalytic residues depicted as red sticks, mutated residues as orange sticks, wild-type residues as cream sticks, and stabilizing pockets as magenta surfaces. αLys135 (mutated) and αGlu135 (wild-type) both do not interact with the hydratase catalytic site (B bottom left). The distance between the α-carbon of βAla233 and α235 increases from 6.6 Å (αArg235) to 7.9 Å (αTrp235) (B bottom right). βAsp389 increases the distance between thiolase catalytic site residues βC458, βC138, and βH428 (C bottom center). βSer430 interferes with a stabilizing pocket near the catalytic site (C bottom right). The loss of proline’s conformational rigidity induced by βArg294 may affect protein tertiary structure (C bottom left). Cartoon representation of all 5 missense mutations as solid ribbon models (D). Residues represented as in panels B and C.