Mitochondria, once viewed as the "simple" powerhouse of the cell, are increasingly recognized to be involved in many different cell biological processes that involve interaction with non-mitochondrial organelles such as the endoplasmic reticulum and plasma membrane. These interactions take place in part via machinery on the mitochondrial surface that generates and senses protein and lipid signals, which has been an area of focus for us in the context of mitochondrial dynamics (fusion) and changes in energetic in response to extracellular signaling events. Our recent work has uncovered a new role for mitochondria in a specialized form of RNA processing that appears to take place at the interface between the mitochondrial surface and juxtaposed RNA granules. More specifically, we have linked a signaling enzyme on the mitochondrial surface to the production of piRNAs, a third type of RNAi, in an electron-dense structure known as nuage that is similar to P-bodies. Using cell biological, in culture, and animal model approaches, we propose to study how lipid signaling at the mitochondrial surface promotes this newly identified physical and functional interaction between mitochondria and RNA-processing complexes via underlying mechanisms that potentially include kinesin-regulated trafficking of RNAs, processing granules and mitochondria on microtubules. Relevance: This initial story applies to a pathway that is critical for spermatogenesis, has relevance to male infertility, and offers opportunities fr a novel type of male contraceptive. However, other types of RNA recruitment to and processing at the mitochondrial surface are known and represent a broader context in which this newly identified pathway will likely be important, including in connection to mesenchymal stem cells, brain and cardiac function, and cancer.

Public Health Relevance

Mobilization of transposons can cause genetic diseases including cancer. piRNAs, the third type of RNAi discovered, function to maintaining genome integrity by suppressing transposon mobilization and performing germ-line imprinting. We have found that mitochondria play a role in generation of piRNAs via the action of a signaling enzyme anchored on the mitochondrial surface. We propose to increase our understanding of how a signal generated on the mitochondrial surface regulates this process, which may involve controlling how mitochondria and the RNA structures traffic through the cell on microtubules. If successful, the proposed research could facilitate the development of tools to broadly manipulate the epigenetic structure of genes and thus control their expression, might identify some causes of male infertility, and will present a potential therapeutic opportunity for a male contraceptive. It may also be important more broadly, as piRNAs are now being reported in many tissues.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM100109-03
Application #
8726437
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Ha, Elizabeth E-J; Frohman, Michael A (2014) Regulation of mitochondrial morphology by lipids. Biofactors 40:419-24
Zhang, Yi; Frohman, Michael A (2014) Cellular and physiological roles for phospholipase D1 in cancer. J Biol Chem 289:22567-74