Barth syndrome mutations that cause tafazzin complex lability.

Area of Science:

• Mitochondrial biology
• Human genetics
• Molecular medicine

Background:

• Mitochondrial dysfunction underlies numerous human diseases.
• Barth syndrome (BTHS) is an X-linked disorder caused by mutations in the TAZ1 gene, encoding tafazzin (Taz1p).
• Taz1p is crucial for cardiolipin metabolism, a key mitochondrial phospholipid.

Purpose of the Study:

• To investigate the functional consequences of TAZ1 mutations in a yeast model.
• To determine the molecular mechanisms underlying tafazzin dysfunction in BTHS.
• To explore potential therapeutic strategies by modulating protein stability.

Main Methods:

• Established a yeast mutant tafazzin panel representing BTHS missense mutations.
• Utilized protein expression analysis, protease degradation assays, and complex assembly studies.
• Assessed mutant tafazzin function in the presence and absence of the i-AAA protease.

Main Results:

• 18 of 21 BTHS missense mutations failed to functionally complement endogenous tafazzin.
• Four mutant tafazzins were degraded due to misfolding, mediated by the i-AAA protease.
• Despite normal complex assembly, BTHS mutant complexes exhibited extreme instability and aggregation.
• Inhibition of i-AAA protease partially restored function by increasing expression and assembly.

Conclusions:

• Loss of tafazzin function in BTHS is primarily due to the inherent instability of mutant protein complexes.
• Protein misfolding and subsequent degradation contribute to tafazzin deficiency.
• Targeting protease activity offers a potential avenue for ameliorating BTHS phenotypes.