It was recently discovered that reduced ETC signaling in neuronal cells is sufficient to extend the lifespan of C. elegans. It was also found that this effect is dependent upon the activity of an essential component of the mitochondrial stress response or UPRmt. It is not yet understood, however, the fundamental mechanisms by which this life span extension occurs or how the signal is sent and perceived. Moreover, the essential role that the mitochondrion has in cellular homeostasis and energy production suggests that it may act as a reactive sensor of random intrinsic or extrinsic variables capable of influencing an organism's susceptibility to disease. Changes within the mitochondria thus also might be responsible for the emergent properties displayed in such a system in response to stochastic changes, and/or may play a significant role in coordinating the activation of non-mitochondrial stress response pathways. A prediction that genetic modifications will decrease the capacity for stochastic variation in mitochondrial function will ultimately negatively affect the fitness of the organism. Such a hypothesis is in keeping with recent evidence suggesting that deleterious mutations actually decrease the sensitivity of gene expression in response to small environmental changes (a loss of phenotypic robustness). A further hypothesis is it may predict co-variance between the UPRmt and stress response pathways, currently thought to act in distinct regulatory networks, and seek to discover the potential mechanisms by which this co-variance occurs.
The endosymbiotically-derived relationship between the mitochondria and cell initially provided the cell with the energy necessary to allow for differentiation and to eventually enter into a state of complexity in which specialized organs and tissues could evolve. Two billion years later, whole organisms composed of complex networks of organs, tissues, and cells, are utterly dependent upon mitochondria for their energetic functions. In the face of an increasingly complex environment, the eukaryotic cell now spends a considerable amount of mitochondrial-derived energy in an attempt to coordinate homeostasis and to minimize the potential for stochastic events to disrupt whole organism function leading to disease.
| Zhang, Qian; Wu, Xueying; Chen, Peng et al. (2018) The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling. Cell 174:870-883.e17 |
| Tian, Ye; Garcia, Gilberto; Bian, Qian et al. (2016) Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR(mt). Cell 165:1197-1208 |
| Kim, Hyun-Eui; Grant, Ana Rodrigues; Simic, Milos S et al. (2016) Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response. Cell 166:1539-1552.e16 |
| Douglas, Peter M; Baird, Nathan A; Simic, Milos S et al. (2015) Heterotypic Signals from Neural HSF-1 Separate Thermotolerance from Longevity. Cell Rep 12:1196-1204 |
| Schinzel, Robert; Dillin, Andrew (2015) Endocrine aspects of organelle stress—cell non-autonomous signaling of mitochondria and the ER. Curr Opin Cell Biol 33:102-10 |
| Wolff, Suzanne; Weissman, Jonathan S; Dillin, Andrew (2014) Differential scales of protein quality control. Cell 157:52-64 |
