LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation

Patrick J. Doonan, Harish C. Chandramoorthy, Nicholas E. Hoffman, Xueqian Zhang, César Cárdenas, Santhanam Shanmughapriya, Sudarsan Rajan, Sandhya Vallem, Xiongwen Chen, J. Kevin Foskett, Joseph Y. Cheung, Steven R. Houser, Muniswamy Madesh

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Dysregulation of mitochondrial Ca2+-dependent bioenergetics has been implicated in various pathophysiological settings, including neurodegeneration and myocardial infarction. Although mitochondrial Ca2+ transport has been characterized, and several molecules, including LETM1, have been identified, the functional role of LETM1-mediated Ca2+ transport remains unresolved. This study examines LETM1-mediated mitochondrial Ca2+ transport and bioenergetics in multiple cell types, including fibroblasts derived from patients with Wolf-Hirschhorn syndrome (WHS). The results show that both mitochondrial Ca2+ influx and efflux rates are impaired in LETM1 knockdown, and similar phenotypes were observed in δEF hand, D676A D688KLETM1 mutant-overexpressed cells, and in cells derived from patients with WHS. Although LETM1 levels were lower in WHS-derived fibroblasts, the mitochondrial Ca2+ 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 Ca2+ transport and bioenergetics. These findings reveal the role of LETM1-dependent mitochondrial Ca2+ flux in shaping cellular bioenergetics.-Doonan, P J., Chandramoorthy, H. C., Hoffman, N. E., Zhang, X., Cárdenas, C., Shanmughapriya, S., Rajan, S., Vallem, S., Chen, X., Foskett, J. K., Cheung, J. Y., Houser, S. R., Madesh, M. LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation.

Original languageEnglish (US)
Pages (from-to)4936-4949
Number of pages14
JournalFASEB Journal
Volume28
Issue number11
DOIs
StatePublished - Nov 1 2014

Keywords

  • Cell cycle
  • Metabolism
  • Reactive oxygen species
  • Wolf-Hirschhorn syndrome

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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