Monday, May 19, 2025
5/19/2025
A novel mitochondria-to-lysosome stress signaling pathway in degenerative disease and aging - This application synergizes expertise from two groups, with one specialized in mitochondrial biology and proteostatic signaling and the other in V-ATPase biochemistry and vacuolar/lysosomal biology. Mitochondria are multifunctional organelles. In addition to their major role in ATP production, mitochondria are also involved in other cellular processes including stress signaling and cell death. However, under many pathophysiological conditions and during aging, to what extent impairment to non-bioenergetic mitochondrial functions contributes to the decline of cell fitness is poorly understood. We found that various mitochondrial stressors can directly induce proteostatic stress in the cytosol independent of energy metabolism, by a mechanism named mitochondrial Precursor Overaccumulation Stress (mPOS). The mechanisms by which mPOS affects cellular function and viability remain unknown so far. The lysosome (or vacuole in yeast) also carries out many cellular functions in the cell, including pH control, ion and amino acid homeostasis, protein degradation, autophagy and vesicular trafficking. Interestingly, defects in mitochondrial and lysosomal functions can both contribute to cell aging and aging-associated degenerative disorders, including Parkinson’s disease and amyotrophic lateral sclerosis. This odd coincidence invites the question of whether damage to mitochondria and lysosomes can synergize, either sequentially or additively, to affect a common cellular process critical for the fitness and survival of aged cells. To address this question, it is important to comprehensively describe how mitochondria and lysosomes interact at the molecular level to affect cellular functions. In this application, we focus on a novel mitochondria-to-lysosome stress signaling pathway, in which mitochondrial defects cause proteostatic stress to the vacuole/lysosome thereby affecting cell survival. The scientific premise of this application is based on our strong preliminary data from studies in yeast, cultured human cells and transgenic mice. More specifically, the Aim 1 of the proposal will test the hypothesis that specific mitochondrial stress can cause severe proteostatic damage to the yeast vacuole. The genetic amenability of the yeast system will enable us to discover genes that suppress the mitochondria-to-vacuole stress signaling and possibly, extend cell’s lifespan. In Aim 2, we will validate this novel mitochondria-to-lysosome stress signaling pathway in cultured mammalian cells. In Aim 3, we will test the hypothesis that mitochondrial stress causes lysosomal damage and affects tissue homeostasis in vivo, using a unique mouse model that we recently developed. We will determine the mechanism of the mitochondria-induced lysosomal damage in post-mitotic tissues. Success of our experiments may unravel a novel mechanism of cell demise that involves mitochondria-to-lysosome stress signaling. The results may ultimately help the better understanding of many aging-associated diseases that are co-manifested by mitochondrial and lysosomal defects.
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