Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria

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The activity and morphology of mitochondria are maintained by dynamic fusion and fission processes regulated by a group of proteins residing in, or attached to, their inner and outer membranes. Hypoxia-induced gene domain protein-1a (Higd-1a)/HIMP1-a/HIG1, a mitochondrial inner membrane protein, plays a role in cell survival under hypoxic conditions. In the present study, we showed that Higd-1a depletion resulted in mitochondrial fission, depletion of mtDNA, disorganization of cristae, and growth retardation. We demonstrated that Higd-1a functions by specifically binding to Optic atrophy 1 (Opa1), a key element in fusion of the inner membrane. In the absence of Higd-1a, Opa1 was cleaved, resulting in the loss of its long isoforms and accumulation of small soluble forms. The small forms of Opa1 do not interact with Higd-1a, suggesting that a part of Opa1 in or proximal to the membrane is required for that interaction. Opa1 cleavage, mitochondrial fission, and cell death induced by dissipation of the mitochondrial membrane potential were significantly inhibited by ectopic expression of Higd-1a. Furthermore, growth inhibition due to Higd-1a depletion could be overcome by overexpression of a noncleavable form of Opa1. Collectively, our observations demonstrate that Higd-1a inhibits Opa1 cleavage and is required for mitochondrial fusion by virtue of its interaction with Opa1.
Publisher
NATL ACAD SCIENCES
Issue Date
2013-08
Language
English
Article Type
Article
Keywords

CYTOCHROME-C RELEASE; M-AAA PROTEASE; PROTEOLYTIC CLEAVAGE; MAMMALIAN HOMOLOGS; GENE-EXPRESSION; OPTIC ATROPHY; FUSION; APOPTOSIS; CELLS; PROHIBITINS

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.110, no.32, pp.13014 - 13019

ISSN
0027-8424
DOI
10.1073/pnas.1307170110
URI
http://hdl.handle.net/10203/189544
Appears in Collection
CH-Journal Papers(저널논문)
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