Investigating the relationship between mitochondrial dysfunction and apoptosis, autophagy and cellular senescence

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In addition to energy production, the mitochondria play a crucial role in apoptosis, autophagy and senescence. The relationship/crosstalk between redox signaling, autophagy, senescence and mitochondrial dysfunction is not well understood. It is hypothesized that accumulation of toxic proteins (oxidized or nitrosylated) and malfunctioning of mitochondrion lead to further oxidative stress that could lead to any of the aforementioned phenomena. Autophagy is induced in response to such stress in order to eliminate dysfunctional proteins and organelles. However, if autophagy is inhibited, cell death (in the neuronal system) or senescence (in fibroblasts) is activated. Using normal human fibroblasts with wild type and Presenilin-1 mutations as models, the research program is set to investigate the mechanism of cellular switches that trigger senescence, apoptosis and autophagy and role of mitochondria in these processes. Relevant to the proposed program, we have developed an excellent cellular model of primary human skin fibroblasts (NHFs) with wild type presenilin-1 (PS-1) and those with mutated PS-1 for the study of the three phenomenons1. We have established that the NHFs with PS-1 mutation have: a) increased production of reactive oxygen species (ROS); b) upregulation of MnSOD, p21, p16, and Rb, leading to premature senescence and downregulation of proliferating cell nuclear antigen (PCNA); c) decreased levels of autophagy; d) resistance to apoptosis caused by external oxidative stress. Furthermore, we discovered that water-soluble CoQ10 (WS CoQ10) inhibits premature senescence in PS-1 mutant cells and causes resumption of autophagy in these cells1. However, the exact deficiency in the mitochondrial function due to the PS-1 mutation is still not understood, the biochemical switch for the induction of either senescence or autophagy in response to increased generation of ROS remains unknown. How does WS CoQ10 restore autophagic induction in PS-1 mutated fibroblasts remains a very important and interesting question, yet to be answered. In order to address the aforementioned knowledge gap, this program proposes the following research aims: 1) Investigation of mitochondrial dysfunction in PS-1 mutated fibroblasts (PSMF). 2. Characterization of signalling cascades from mitochondrial oxidative stress to senescence, autophagy, or apoptosis. Successful completion of this program will lead to our advancement of understanding of the mechanism of senescence, autophagy, and apoptosis and the intricate relationship between these fundamental cellular processes.