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Doonan 2014 FASEB J

From Bioblast
Publications in the MiPMap
Doonan PJ, Chandramoorthy HC, Hoffman NE, Zhang X, Cárdenas C, Shanmughapriya S, Rajan S, Vallem S, Chen X, Foskett JK, Cheung JY, Houser SR, Madesh M (2014) LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB J 28:4936-49.

» PMID: 25077561 Open Access

Doonan Patrick J, Chandramoorthy Harish C, Hoffman Nicholas E, Zhang Xueqian, Cardenas Cesar, Shanmughapriya Santhanam, Rajan Sudarsan, Vallem Sandhya, Chen Xiongwen, Foskett JK, Cheung JosephY, Houser Steven R, Madesh Muniswamy (2014) FASEB J

Abstract: Dysregulation of mitochondrial Ca(2+)-dependent bioenergetics has been implicated in various pathophysiological settings, including neurodegeneration and myocardial infarction. Although mitochondrial Ca(2+) transport has been characterized, and several molecules, including LETM1, have been identified, the functional role of LETM1-mediated Ca(2+) transport remains unresolved. This study examines LETM1-mediated mitochondrial Ca(2+) transport and bioenergetics in multiple cell types, including fibroblasts derived from patients with Wolf-Hirschhorn syndrome (WHS). The results show that both mitochondrial Ca(2+) influx and efflux rates are impaired in LETM1 knockdown, and similar phenotypes were observed in ΔEF hand, (D676A D688K)LETM1 mutant-overexpressed cells, and in cells derived from patients with WHS. Although LETM1 levels were lower in WHS-derived fibroblasts, the mitochondrial Ca(2+) uniporter components MCU, MCUR1, and MICU1 remain unaltered. In addition, the MCU mitoplast patch-clamp current (IMCU) was largely unaffected in LETM1-knockdown cells. Silencing of LETM1 also impaired basal mitochondrial oxygen consumption, possibly via complex IV inactivation and ATP production. Remarkably, LETM1 knockdown also resulted in increased reactive oxygen species production. Further, LETM1 silencing promoted AMPK activation, autophagy, and cell cycle arrest. Reconstitution of LETM1 or antioxidant overexpression rescued mitochondrial Ca(2+) transport and bioenergetics. These findings reveal the role of LETM1-dependent mitochondrial Ca(2+) flux in shaping cellular bioenergetics. Keywords: Wolf-Hirschhorn syndrome; cell cycle; metabolism; reactive oxygen species. Bioblast editor: Cecatto C


Labels: MiParea: Genetic knockout;overexpression  Pathology: Inherited  Stress:Oxidative stress;RONS 



Regulation: Calcium 



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