Premium
LETM1 is an essential component of mitochondrial calcium uptake and regulation of cellular bioenergetics
Author(s) -
Doonan Patrick John,
Mallilankaraman Karthik,
Chandramoorthy Harish,
Madesh Muniswamy
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb209
Subject(s) - bioenergetics , gene knockdown , microbiology and biotechnology , mitochondrion , biology , chemistry , mitochondrial ros , inner mitochondrial membrane , biochemistry , apoptosis
Regulation of mitochondrial Ca 2+ ‐dependent cellular bioenergetics has been implicated in a variety of pathophysiological settings including neurodegeneration, myocardial infarction and immunity. Recently, LETM1 was proposed as a mitochondrial Ca 2+ /H + antiporter; however characterization of the functional role of LETM1‐mediated Ca 2+ transfer has yet to be studied. Here we demonstrate that LETM1 knockdown significantly impairs mitochondrial Ca 2+ uptake and results in bioenergetic collapse. We observed that mitochondrial Ca 2+ uptake is impaired in shRNA‐mediated LETM1 knockdown and ΔEF hand LETM1 and D676AD688K LETM1 overexpression cells. Knockdown of LETM1 promotes LC3 positive multilamellar vesicle formation, indicative of autophagy induction. Furthermore, cellular bioenergetic parameters including ATP and oxygen consumption were reduced. In contrast, cellular NADH and mitochondrial membrane potential were unaltered in both control and shRNA LETM1 cells. Interestingly, knockdown of LETM1 by siRNA in primary neonatal cardiomyocytes resulted in a remarkable change in mitochondrial morphology and reduced Ca 2+ uptake. We also observed that LETM1 knockdown results in increased ROS production. Our results represent the first time that LETM1 has been linked to cellular bioenergetics through regulation of mitochondrial Ca 2+ . Supported by NIH R01 HL086699 , HL086699 ‐01A2S1, 1S10RR027327‐01