Facioscapulohumeral Dystrophy (FSHD) is one of the most common age-related degenerative muscle diseases characterized by the progressive weakening and loss of skeletal muscle. It is caused by transcriptional derepression at the 4q35 subtelomeric region as a result of DNA repeat contraction, hypomethylation and telomere shortening. ANT1, FRG1, FRG2 and DUX4 are the four possibly derepressed 4q35 genes. Although much attention has been focused on the transcriptional activation of DUX4, encoding a homeodomain protein of unknown function, recent studies showed that DUX4 expression is not sufficient to induce muscle pathology in a mouse model. This raises the possibility that other 4q35 genes may contribute to FSHD pathogenesis, either independently or synergistically. Indeed, accumulating evidence indicates that FSHD is consistently associated with oxidative stress and mitochondrial dysfunction, supporting a role for ANT1. ANT1 is the only 4q35 gene known to be involved in mitochondrial function, oxidative stress and muscle disease. ANT1 encodes the muscle/heart isoform of adenine nucleotide translocase (Ant1), involved in ATP/ADP exchange across the mitochondrial inner membrane. Ant1 protein is unusually abundant and accounts for ~6% of the total protein in muscle mitochondria. We hypothesize that Ant1 over-expression may cause protein overloading and proteostatic stress on the inner membrane, which in turn affects mitochondrial function and leads to muscle degeneration. However, the high abundance of the endogenous Ant1 poses a significant challenge for over-expression studies using transgenic animals to validate the ANT1 pathogenesis model. Although ANT1 transgenic mice have been generated, these studies did not demonstrate that the transgene was expressed to a level exceeding that of endogenous Ant1. Not surprisingly, no obvious muscle pathology was observed in these animals. Thus, it remains unclear whether Ant1 over-expression is pathogenic. Here, we propose to use an unconventional transgenic strategy to prepare mouse lines that unambiguously over-express Ant1. This will allow us to reevaluate the potential role of over-expressed Ant1 in inducing mitochondrial damage, oxidative stress and muscle degeneration. More specifically, we will (1) test the hypothesis that Ant1 over-expression induces progressive skeletal muscle loss, physical disability, mitochondrial damage, bioenergetic defects and muscle pathology, and (2) determine the mechanism(s) of mitochondrial damage induced by Ant1 over-expression. The results will help us better understanding the pathogenic mechanism of FSHD. It will also provide a valuable animal model for developing therapeutic drugs for the treatment of this common muscle degenerative disease which is estimated to affect ~500,000 people worldwide.
Facioscapulohumeral Dystrophy (FSHD) is one of the most common age-related progressive muscle disorders. We propose to generate a mouse model and to test the hypothesis that over-expression of adenine nucleotide translocase 1 (Ant1), the most abundant protein in mitochondria, may cause mitochondrial damage, oxidative stress and muscle degeneration in FSHD. The results will help better understanding the pathogenic mechanism of FSHD and provide a valuable tool for developing therapeutic drugs for the treatment of the disease.
| Coyne, Liam P; Chen, Xin Jie (2018) mPOS is a novel mitochondrial trigger of cell death - implications for neurodegeneration. FEBS Lett 592:759-775 |
| Chen, Xin Jie; Clark-Walker, George Desmond (2018) Unveiling the mystery of mitochondrial DNA replication in yeasts. Mitochondrion 38:17-22 |
| Liu, Yaxin; Wang, Xiaowen; Chen, Xin Jie (2015) Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases. Mol Biol Cell 26:1985-94 |
| Wang, Xiaowen; Chen, Xin Jie (2015) A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524:481-4 |
