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

Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13014-9. doi: 10.1073/pnas.1307170110. Epub 2013 Jul 22.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Blotting, Western
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Potential, Mitochondrial / genetics
  • Membrane Potential, Mitochondrial / physiology*
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein Binding
  • RNA Interference

Substances

  • HIGD1A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Neoplasm Proteins
  • Adenosine Triphosphate
  • GTP Phosphohydrolases
  • OPA1 protein, human