Mitochondrial function degenerates with aging. The overall goals of our proposal are (1) to better understand how aging induces mitochondrial degeneration and (2) to identify cellular pathways other than the currently known anti-oxidative mechanisms that can potentially delay the degenerative process. In the previous grant period, we developed a yeast model for the adult/late-onset neuromuscular degenerative disease autosomal dominant Progressive External Ophthalmoplegia (adPEO), caused by gain-of-function mutations in the adenine nucleotide translocase (Ant). Ant is normally involved in ADP/ATP exchange across the mitochondrial inner membrane. We found that equivalent mutations in yeast induce aging-dependent mitochondrial depolarization and -aging prohibitin mutants. These unique experimental systems enabled us to unequivocally demonstrate that reducing cytosolic protein synthesis can robustly suppress aging-dependent mitochondrial degeneration. This finding reveals an unanticipated link between cellular protein homeostasis (or proteostasis) and the functional integrity of mitochondria. In a recent genetic screen for anti-degenerative suppressors, we identified genes involved in cytosolic mRNA decay and protein degradation. Several of these proteostatic genes/pathways have human orthologs known to be mutated in degenerative diseases. These observations led to our central hypothesis that loss of protein homeostasis in the cytosol may induce proteostatic stress on the mitochondrial inner membrane, which consequently affects energy homeostasis and the fitness of aged cells. To test this, we propose the following aims: (1) We will examine the link between cellular proteostasis and mitochondrial integrity during replicative aging. We will specifically determine whether defects in mRNA decay and protein degradation, which cause protein phenotypically tractable degenerative cell death. These phenotypes were also independently captured in the pro overloading from the cytosol, can generally accelerate aging-dependent mitochondrial degeneration;(2) We will test the hypothesis that cytosolic proteostatic stress may affect protein homeostasis, respiratory complex biogenesis, bioenergetic efficiency and structural integrity of the mitochondrial inner membrane;and (3) By taking advantage of the anti-degenerative genes identified in our study, we will examine whether over-expression of these genes, which improves mitochondrial membrane integrity and energy transduction, extends cell's lifespan. Because decline of cellular proteostasis is a common molecular symptom of aging and some degenerative diseases, our studies may help us better understand the mechanism of mitochondrial degeneration under these conditions.
The mitochondrion is known as the powerhouse of the cell and its function degenerates with aging and in aging-related degenerative disorders. We aim to identify evolutionarily conserved cellular pathways that can delay the aging-dependent degeneration of mitochondria and improve energy homeostasis in aged cells. These anti-degenerative pathways may be potentially used as intervention targets for delaying the onset and progression of mitochondrial degeneration.
|Wang, Xiaowen; Chen, Xin Jie (2015) A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524:481-4|
|La, Thuy; Clark-Walker, George Desmond; Wang, Xiaowen et al. (2013) Mutations on the N-terminal edge of the DELSEED loop in either the Î± or Î² subunit of the mitochondrial F1-ATPase enhance ATP hydrolysis in the absence of the central Î³ rotor. Eukaryot Cell 12:1451-61|
|Wang, Xiaowen; Mbantenkhu, MacMillan; Wierzbicki, Sara et al. (2013) Preparation of the Mgm101 recombination protein by MBP-based tagging strategy. J Vis Exp :|
|Chen, Xin Jie (2013) Mechanism of homologous recombination and implications for aging-related deletions in mitochondrial DNA. Microbiol Mol Biol Rev 77:476-96|
|Mbantenkhu, MacMillan; Wierzbicki, Sara; Wang, Xiaowen et al. (2013) A short carboxyl-terminal tail is required for single-stranded DNA binding, higher-order structural organization, and stability of the mitochondrial single-stranded annealing protein Mgm101. Mol Biol Cell 24:1507-18|
|Liu, Yaxin; Chen, Xin Jie (2013) Adenine nucleotide translocase, mitochondrial stress, and degenerative cell death. Oxid Med Cell Longev 2013:146860|
|Nardozzi, Jonathan D; Wang, Xiaowen; Mbantenkhu, MacMillan et al. (2012) A properly configured ring structure is critical for the function of the mitochondrial DNA recombination protein, Mgm101. J Biol Chem 287:37259-68|
|Mbantenkhu, MacMillan; Wang, Xiaowen; Nardozzi, Jonathan D et al. (2011) Mgm101 is a Rad52-related protein required for mitochondrial DNA recombination. J Biol Chem 286:42360-70|
|Chen, Xin Jie (2011) The search for nonconventional mitochondrial determinants of aging. Mol Cell 42:271-3|
|Kucejova, Blanka; Li, Li; Wang, Xiaowen et al. (2008) Pleiotropic effects of the yeast Sal1 and Aac2 carriers on mitochondrial function via an activity distinct from adenine nucleotide transport. Mol Genet Genomics 280:25-39|
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