Mitochondria perform fundamental functions in eukaryotic cells, including ATP production via respiration and cellular ion and phospholipid homeostasis. They also serve as platforms to integrate signaling pathways such as cell death and innate immunity. Mitochondrial functions are tightly linked to mitochondrial form, established through separate, but somehow coordinated machines that control dynamics, positioning, motility and mitochondrial DNA (mtDNA) transmission. The endoplasmic reticulum (ER) has emerged as an integral and pervasive player in the regulation of mitochondrial form and function. The ER exerts its role through contacts with mitochondria, which we hypothesize create specialized microdomains, which can recruit and/or modulate effectors that control and integrate mitochondrial physiology with other organelles and signaling pathways. In most cases, however, the molecular composition of ER-mitochondria contacts is poorly defined and their exact mechanisms of action, their functional scope and modes of communication are poorly understood. In the aims of this grant, we will address these deficits by exploring the molecular basis and functions of different types of ER-mitochondria contact sites in yeast and we will extend our findings to mammalian cells using comparative and forward strategies. New information in this area of cell biology will provide insight into the general architecture and rols of ER contacts and their regulation of mitochondrial function and cellular homeostasis to more accurately reveal role of mitochondria in human diseases that result from mitochondrial and ER dysfunction.

Public Health Relevance

Increasing evidence indicates that contacts formed between two major eukaryotic cellular organelles - the endoplasmic reticulum (ER) and mitochondria - are regulatory hubs essential for cell homeostasis. Although their pervasive significance for cell is established, they are poorly understood on both the molecular and functional levels - a deficit that is directly addressed by this grant. Insight into the mechanisms of action, functional scope and modes of communication of ER-mitochondria contact sites will pave the way for a better understanding of the etiology of human diseases associated with mitochondrial and ER dysfunction and could reveal new targets for therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM097432-08
Application #
9471389
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Anderson, Vernon
Project Start
2011-09-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Horenkamp, Florian A; Valverde, Diana P; Nunnari, Jodi et al. (2018) Molecular basis for sterol transport by StART-like lipid transfer domains. EMBO J 37:
Murley, Andrew; Yamada, Justin; Niles, Bradley J et al. (2017) Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling. J Cell Biol 216:2679-2689
Murley, Andrew; Nunnari, Jodi (2016) The Emerging Network of Mitochondria-Organelle Contacts. Mol Cell 61:648-653
Lewis, Samantha C; Uchiyama, Lauren F; Nunnari, Jodi (2016) ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353:aaf5549
Murley, Andrew; Sarsam, Reta D; Toulmay, Alexandre et al. (2015) Ltc1 is an ER-localized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts. J Cell Biol 209:539-48