Abstract #96C

Molecular Pathways Regulating Aging-dependent Mitochondrial Degeneration. Xin Jie Chen, Xiaowen Wang, Xiaoming Zuo, Blanka Kucejova. Department of Molecular Biolog, UT Southwestern Medical Center, Dallas, TX.
   Mitochondrial function degenerates in numerous aging-associated neuromuscular diseases and in biologically aged cells. One of the current models proposes that accumulation of deleterious “aging factors” in old cells may induce mitochondrial degeneration and send the cells onto the degenerative road. To understand the nature of the “aging factors” and how these factors control mitochondrial degeneration, we modeled the human late-onset degenerative disease, adPEO (autosomal dominant Progressive External Ophthalmoplegia), by introducing pathogenic mutations in the yeast adenine nucleotide translocase, Aac2p. The mutant Aac2p was found to induce mitochondrial depolarization and aging-dependent degenerative cell death. This yeast-based system enabled us to undertake genome-wide screens for molecular pathways that suppress or accelerate the aging-dependent mitochondrial degeneration. We found that conditions favoring the accumulation of unassembled proteins on the mitochondrial inner membrane are strong inducers for the aac2-induced mitochondrial degeneration. Interestingly, mitochondrial degeneration is suppressed by over-expression of the histone deacetylase (HDAC) complex involving Rpd3p and Rco1p, which is known to suppress cytosolic ribosomal biogenesis. Genetic and pharmacological interventions that directly suppress cytosolic ribosomal function also delay the onset of mitochondrial degeneration. Furthermore, we showed that mitochondrial degeneration is suppressed by nutrient limitations, by down-regulating the nutrient-sensing TOR, PKA and Sch9 signaling pathways, and by application of mild stresses. All these conditions are known to reduce ribosomal biogenesis concomitant with an effect in extending the replicative lifespan of the cell. We propose that mitochondrial Unassembled Protein Stress (mUPS) is a significant aging-factor in old cells and that alleviating mitochondrial stress from protein overloading is a common feature shared by the lifespan-extending interventions. This work is supported by grants from NIH (R01-AG023731) and AHA (0435047N) to X.J.C.

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