[R01] Molecular Mechanisms of Mitochondrial Calcium Exchange in the Heart
Ente: National Heart Lung and Blood Institute
Scadenza: 2031-05-31
Importo max: 625.035 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Cardiovascular disease is a leading cause of death in the United States and worldwide. Ischemic heart disease
(IHD) is caused by partial or complete occlusion of coronary arteries, disrupting blood flow to the heart and
causing tissue damage. Reperfusion of the heart restores blood flow, but it also triggers a reperfusion injury, a
second phase of tissue damage which can account for up to 50% of the final infarct size. Mild ischemia
reperfusion (I/R) injury allows for recovery, however severe I/R injuries lead to heart failure (HF) and death. The
incidence of IHD and HF are increasing, and there is no current therapy to mitigate I/R injury. Tissue damage in
I/R injury is caused by mitochondria-dependent cell death, which is initiated by mitochondrial calcium (Ca2+MITO)
overload. Preventing Ca2+MITO overload in I/R injury is a strategy to mitigate tissue damage, however this has
been hindered by an incomplete understanding of Ca2+MITO transport mechanism. The mitochondrial Ca2+
uniporter (MCU-)complex is the only identified mechanism for Ca2+MITO uptake, however heart mitochondria
possess another MCU-independent Ca2+ uptake mechanism with an unknown molecular identity which is
sufficient to drive Ca2+MITO overload in I/R injury. Cardiac mitochondria possess both Na+/Ca2+ and H+/Ca2+
exchange Ca2+MITO efflux pathways, however the proteins which mediate these processes remain controversial.
There are four candidate genes proposed to mediate Ca2+MITO efflux: Nclx, Tmem65, Letm1, and Tmbim5;
however developmental deletion of Nclx, Tmem65, or Tmbim5 does not cause heart dysfunction and Letm1
deletion is embryonically lethal, so little is known about its cardiac role. Recently it was observed LETM1 is
increased in human IHD patient samples, suggesting LETM1 is important in the heart. Our goal is to identify the
proteins mediating mitochondrial H+/Ca2+ and Na+/Ca2+ exchange in the heart and delineate their contributions
to Ca2+MITO homeostasis. The major hypothesis is cardiac Ca2+MITO homeostasis requires H+/Ca2+ exchange
mediated by LETM1 and Na+/Ca2+ exchange mediated by both NCLX and TMEM65. In our preliminary studies
we found cardiac Letm1 deletion caused HF and mitochondrial dysfunction, increased Ca2+MITO levels, and
reduced Ca2+MITO efflux. We have also observed mitochondrial Na+/Ca2+ efflux persists in mitochondria lacking
either Nclx or Tmem65, suggesting neither protein mediates the entire process. In Aim 1 we will study the role
of LETM1 in cardiac physiology, mitochondrial function, H+/Ca2+ exchange, and general cation transport. In Aim
2 we will study the role of LETM1 in I/R injury using a regulatory phosphorylation site (LETM1-pT191) to modulate
LETM1 activity to test if LETM1 is a therapeutic target in IHD. In Aim 3 we will study the relative contributions of
NCLX and TMEM65 to cardiac mitochondrial Na+/Ca2+ exchange to determine which protein(s) mediate this
important process. We will validate our main findings in human-d
Istituzione: BAYLOR COLLEGE OF MEDICINE
PI: Michael Bround
Progetto: 1R01HL187341-01
Settori: National Heart Lung and Blood Institute
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