This project focuses on cardiac signaling pathways in which lipid metabolism, coupled to mitochondrial activity state, promote massive sarcolemma internalization via endocytosis (MEND) and/or massive ectosome shedding (MESS) to the extracellular space. The endocytosis pathway depends on fatty acid metabolism and the generation of cytoplasmic acyl-coenzyme A that is used to lipidate numerous sarcolemmmal proteins. The shedding pathway depends primarily on the generation of lysophosphatidylcholine, the activation of its receptors in the cardiac myocyte, and subsequent scrambling of sarcolemmal phospholipids between monolayers. Both mechanisms appear to depend on the generation of ordered membrane domains within the sarcolemma which then facilitate unique protein-protein interactions and functions. Both mechanisms are expected to play major roles in membrane remodeling that occurs in ischemia/reperfusion injury, as well as in major chronic, degenerative diseases involving oxidative stress. Using multiple mice lines with deficiencies in these pathways, as well as drugs to manipulate individual reactions, we will analyze the commonalities and distinctive traits of these pathways, identify the essential molecular players, factors that decisively push the sarcolemma to MEND or MESS, and define more precisely the physiological and pathological roles of MEND and MESS. The project will provide insight into fundamental cell regulatory mechanisms that have a high impact for an understanding of the leading causes of death in the developed world.

Public Health Relevance

We recently discovered a cardiac signaling pathway in which mitochondrial metabolism controls the acylation of membrane proteins and thereby can initiate the massive internalization of cardiac surface membrane. We now extend this work to a variant process by which massive amounts of cardiac membrane are shed outwardly to the extracellular space of the heart. We are studying how these pathways are related and regulated, how they are used by the heart, and how they affect cardiac function in normal physiology as well as in life-or-death circumstances.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119843-07
Application #
9920758
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Balijepalli, Ravi C
Project Start
2014-04-01
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Physiology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Schmiege, Philip; Fine, Michael; Li, Xiaochun (2018) The regulatory mechanism of mammalian TRPMLs revealed by cryo-EM. FEBS J 285:2579-2585
Lu, Fang-Min; Hilgemann, Donald W (2017) Na/K pump inactivation, subsarcolemmal Na measurements, and cytoplasmic ion turnover kinetics contradict restricted Na spaces in murine cardiac myocytes. J Gen Physiol 149:727-749
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