Maspin binds to cardiolipin in mitochondria and triggers apoptosis

Nitin Mahajan, Brandon Hoover, Manohary Rajendram, Heidi Y. Shi, Kiyoshi Kawasaki, Douglas B. Weibel, Ming Zhang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

A central question in cell biology is how cells respond to stress signals and biochemically regulate apoptosis. One critical pathway involves the change of mitochondrial function and release of cytochrome c to initiate apoptosis. In response to apoptotic stimuli, we found that maspin—a noninhibitory member of the serine protease inhibitor superfamily—translocates from the cytosol to mitochondria and binds to cardiolipin in the inner mitochondrial membrane. Biolayer interferometry assay revealed that recombinant maspin binds cardiolipin with an apparent Kd,of ∼15.8 µM and competes with cytochrome c (apparent of ∼1.31 µM) for binding to cardiolipin-enriched membranes. A hydrophobic, lysine-rich domain in maspin consists of 27 aa, is located at position 268–294, and is responsible for the interaction of this protein with cardiolipin. Depletion of cardiolipin in cells significantly prevents maspin binding to the inner mitochondrial membrane and decreases cytochrome c release and apoptosis. Alteration to maspin's cardiolipin binding domain changes its ability to bind cardiolipin, and tumor cells expressing this mutant have a low frequency of apoptosis. We propose a model of apoptosis in which maspin binds to cardiolipin, displaces cytochrome c from the membrane, and facilitates its release to the cytoplasm.—Mahajan, N., Hoover, B., Rajendram, M., Shi, H. Y., Kawasaki, K., Weibel, D. B., Zhang, M. Maspin binds to cardiolipin in mitochondria and triggers apoptosis. FASEB J. 33, 6354–6364 (2019). www.fasebj.org.

Original languageEnglish (US)
Pages (from-to)6354-6364
Number of pages11
JournalFASEB Journal
Volume33
Issue number5
DOIs
StatePublished - May 1 2019

Keywords

  • anionic phospholipids
  • cytochrome c
  • diphosphatidylglycerol
  • mitochondrial membranes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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