This proposal focuses on the hypothesis that a lipid signaling pathway on the surface of the mitochondria facilitates the process of mitochondrial fission. We have published evidence that the enzyme Lipin 1, which is recruited to the mitochondrial surface by the lipid phosphatidic acid (PA) via a PA-binding domain in the center of the protein, converts the PA to the related signaling lipid diacylglycerol (DAG), which then promotes mitochondrial fission. Unexpectedly, we also found that Lipin 1 harbors a second, cryptic mitochondrial targeting sequence in the catalytic domain that exhibits highly-specific subcellular localization to sites of future fission events. This led to a model that binding to PA triggers a conformational change to expose the second site which avidly targets fission sites on the mitochondrial tubule and robustly triggers fission in a collaborative but also partially independent manner with Drp1, the dynamic-like protein most widely studied as the physical mediator of fission. This topic has direct clinical significance. Manipulation of mitochondrial fission is being tested for therapeutic application in stroke, cardiac ischemia, and pulmonary hypertension;increased knowledge about mechanisms underlying the fission process will aid in development of these approaches. We propose to pursue areas of interest that have been developed in the context of the Lipin 1 - fission story based on exploration of how DAG triggers fission in collaboration with other components of the fission machinery. Such questions include defining the proteins Lipin 1 interacts with at fission sites or recruits to the fission sites through the production of DAG, whether these proteins have roles in the fission process, and whether their function or the fission process itself is driven by DAG production by Lipin 1. We will also examine roles for other members of the Lipin enzyme family in fission, explore how Lipin is recruited to fission sites, and its relationship to the endoplasmic reticulum (ER) and actin cytoskeletal reorganization, which play important roles in the fission process. Taken together, these studies will further our knowledge of the mechanisms underlying fission and be of utility in the development of therapies targeting diseases with connections to this intrinsic process.

Public Health Relevance

Mitochondria, traditionally viewed as the powerhouse of the cell for their role in generation of ATP, are now appreciated to have many other roles in cell functions. During the normal course of events, mitochondria are constantly spitting (undergoing fission) and recombining (fusion), processes that are critical for mitochondrial health and full function. Recent studies from many labs have revealed that manipulating the frequency of mitochondrial fission could have clinical benefit. Decreasing fission can protect cells from dying in conditions of ischemia, such as stroke and vascular insufficiency in the heart. Conversely, fission can stimulate cells to proliferate, which is pathological in conditions such as pulmonary hypertension. Accordingly, learning more about the mechanisms that regulate fission and acquiring ways to control the frequency of fission may be considerable benefit. Our work proposes to examine mechanisms underlying fission with this aim in mind.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM084251-05A1
Application #
8630384
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Chin, Jean
Project Start
2009-01-01
Project End
2018-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$316,000
Indirect Cost
$116,000
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Frohman, Michael A (2015) Role of mitochondrial lipids in guiding fission and fusion. J Mol Med (Berl) 93:263-9
Nelson, Rochelle K; Frohman, Michael A (2015) Physiological and pathophysiological roles for phospholipase D. J Lipid Res 56:2229-37
Frohman, Michael A (2015) The phospholipase D superfamily as therapeutic targets. Trends Pharmacol Sci 36:137-44
Ha, Elizabeth E-J; Frohman, Michael A (2014) Regulation of mitochondrial morphology by lipids. Biofactors 40:419-24
Altshuller, Yelena; Gao, Qun; Frohman, Michael A (2013) A C-Terminal Transmembrane Anchor Targets the Nuage-Localized Spermatogenic Protein Gasz to the Mitochondrial Surface. ISRN Cell Biol 2013:
Ali, Wahida H; Chen, Qin; Delgiorno, Kathleen E et al. (2013) Deficiencies of the lipid-signaling enzymes phospholipase D1 and D2 alter cytoskeletal organization, macrophage phagocytosis, and cytokine-stimulated neutrophil recruitment. PLoS One 8:e55325

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