Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases.
Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases.
复制标题
DOI：
10.1091/mbc.e15-01-0030
复制
发表时间：
2015-06-01
影响因子：
3.3
通讯作者：
Chen XJ
中科院分区：
文献类型：
--
作者：
Liu Y;Wang X;Chen XJ
Missense mutations in membrane proteins cause dominant diseases by unknown mechanisms. Pathogenic mutations in adenine nucleotide translocase 1 affect protein folding and the assembly of multiple protein complexes. The misfolding of one single protein is therefore sufficient to induce proteostatic stress on the membrane. Approximately one-third of proteins in the cell reside in the membrane. Mutations in membrane proteins can induce conformational changes and expose nonnative polar domains/residues to the lipid environment. The molecular effect of the resulting membrane stress is poorly defined. Adenine nucleotide translocase 1 (Ant1) is a mitochondrial inner membrane protein involved in ATP/ADP exchange. Missense mutations in the Ant1 isoform cause autosomal dominant progressive external ophthalmoplegia (adPEO), cardiomyopathy, and myopathy. The mechanism of the Ant1-induced pathologies is highly debated. Here we show that equivalent mutations in the yeast Aac2 protein cause protein misfolding. Misfolded Aac2 drastically affects the assembly and stability of multiple protein complexes in the membrane, which ultimately inhibits cell growth. Despite causing similar proteostatic damages, the adPEO- but not the cardiomyopathy/myopathy-type Aac2 proteins form large aggregates. The data suggest that the Ant1-induced diseases belong to protein misfolding disorders. Protein homeostasis is subtly maintained on the mitochondrial inner membrane and can be derailed by the misfolding of one single protein with or without aggregate formation. This finding could have broad implications for understanding other dominant diseases (e.g., retinitis pigmentosa) caused by missense mutations in membrane proteins.
