title: LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation.
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.
authors: Department of Biochemistry, Center for Translational Medicine.
authors: Patrick J
authors: PJ
authors: Doonan
authors: Department of Biochemistry, Center for Translational Medicine.
authors: Harish C
authors: HC
authors: Chandramoorthy
authors: Department of Biochemistry, Center for Translational Medicine.
authors: Nicholas E
authors: NE
authors: Hoffman
authors: Center for Translational Medicine.
authors: Xueqian
authors: X
authors: Zhang
authors: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile; and.
authors: César
authors: C
authors: Cárdenas
authors: Department of Biochemistry, Center for Translational Medicine.
authors: Santhanam
authors: S
authors: Shanmughapriya
authors: Department of Biochemistry, Center for Translational Medicine.
authors: Sudarsan
authors: S
authors: Rajan
authors: Department of Biochemistry, Center for Translational Medicine.
authors: Sandhya
authors: S
authors: Vallem
authors: Cardiovascular Research Center, and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA;
authors: Xiongwen
authors: X
authors: Chen
authors: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: J Kevin
authors: JK
authors: Foskett
authors: Center for Translational Medicine.
authors: Joseph Y
authors: JY
authors: Cheung
authors: Cardiovascular Research Center, and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA;
authors: Steven R
authors: SR
authors: Houser
authors: Department of Biochemistry, Center for Translational Medicine, madeshm@temple.edu.
authors: Muniswamy
authors: M
authors: Madesh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D004734:Energy Metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D051381:Rats
chemical_list: D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C488528:LETM1 protein, human; C000594750:LETM1 protein, mouse; C000594751:LETM1 protein, rat; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D002118:Calcium
keywords: Wolf-Hirschhorn syndrome; cell cycle; metabolism; reactive oxygen species