N terminus of calpain 1 is a mitochondrial targeting sequence

Rama Krishna Badugu, Matthew Garcia, Vimala Bondada, Aashish Joshi, James W. Geddes

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

The ubiquitous m- and μ-calpains are thought to be localized in the cytosolic compartment, as is their endogenous inhibitor calpastatin. Previously, μ-calpain was found to be enriched in mitochondrial fractions isolated from rat cerebral cortex and SH-SY5Y neuroblastoma cells, but the submitochondrial localization of μ-calpain was not determined. In the present study, submitochondrial fractionation and digitonin permeabilization studies indicated that both calpain 1 and calpain small subunit 1, which together form μ-calpain, are present in the mitochondrial intermembrane space. The N terminus of calpain 1 contains an amphipathic α-helical domain, and is distinct from the N terminus of calpain 2. Calpain 1, but not calpain 2, was imported into mitochondria. Removal of the N-terminal 22 amino acids of calpain 1 blocked the mitochondrial calpain import, while addition of this N-terminal region to calpain 2 or green fluorescent protein enabled mitochondrial import. The N terminus of calpain 1 was not processed following mitochondrial import, but was removed by autolysis following calpain activation. Calpain small subunit 1 was not directly imported into mitochondria, but was imported in the presence of calpain 1. The presence of a mitochondrial targeting sequence in the N-terminal region of calpain 1 is consistent with the localization of μ-calpain to the mitochondrial intermembrane space and provides new insight into the possible functions of this cysteine protease.

Original languageEnglish
Pages (from-to)3409-3417
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number6
DOIs
StatePublished - Feb 8 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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