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

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.

Higd1a is a positive regulator of cytochrome c oxidase

“…Higd1a augments cell survival under hypoxic stress in pancreatic cells (26), and it exerts its protective effect by induction of mitochondrial fission (27). The precise relationship between these reports and our data is not clear.…”

Mitochondria dynamism: of shape, transport and cell migration

“…Mitofilins are inner membrane proteins, which are also involved in the cristae junctions' maintenance [55]; Together with OPA1, they form a complex network required to conserve the mitochondrial cristae structure. Recently, a new protein has been found to be involved in regulating mitochondrial fusion [56]. The hypoxia-induced gene domain protein-1a (Higd-1a) is a mitochondrial inner membrane protein.…”

OPA1 in Cardiovascular Health and Disease

“…However, the over-expression of OPA1 did not appear to protect against ischemia-induced apoptosis and actually worsened it (50). In contrast to these findings, An et al (38) observed that OPA1 overexpression was protective against a hypoxic insult in HEK293T cells. Furthermore, Chen et al (51) noted that murine cardiomyocytes isolated from adult mice were more susceptible to cell death induced by simulated I/R injury suggesting a cardio-protective role for OPA1.…”

“…The exact interaction between ROMO1 and OPA1 is unclear, but it has been proposed that by attenuating oxidative stress, ROMO1 acts to reduce the activation of OMA1 thereby preventing the proteolytic cleavage of OPA1 (36). Finally, Hypoxia-induced gene domain protein 1 (Higd-1a), an IMM protein which has been reported to suppress mitochondrial cytochrome c release and inhibit apoptotic cell death under conditions of hypoxia, has been recently linked to OPA1 function (37,38). It has been shown to bind to and prevent the cleavage of l-OPA1 into s-OPA1, thereby attenuating cytochrome C release and inhibiting carbonyl cyanide-4-phenylhydrazone (FCCP)-induced mitochondrial fission and cell death (38).…”

“…Finally, Hypoxia-induced gene domain protein 1 (Higd-1a), an IMM protein which has been reported to suppress mitochondrial cytochrome c release and inhibit apoptotic cell death under conditions of hypoxia, has been recently linked to OPA1 function (37,38). It has been shown to bind to and prevent the cleavage of l-OPA1 into s-OPA1, thereby attenuating cytochrome C release and inhibiting carbonyl cyanide-4-phenylhydrazone (FCCP)-induced mitochondrial fission and cell death (38). The mechanism through which Higd-1a prevents the proteolysis of OPA1 remains to be determined.…”