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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG024365-08
Application #
8543620
Study Section
Special Emphasis Panel (ZRG1-CB-P (02))
Program Officer
Finkelstein, David B
Project Start
2004-09-01
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$357,848
Indirect Cost
$129,191
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Wolff, Suzanne; Weissman, Jonathan S; Dillin, Andrew (2014) Differential scales of protein quality control. Cell 157:52-64