hFis1, a Novel Component of the Mammalian Mitochondrial Fission Machinery

Abstract

The balance between the fission and fusion mechanisms regulate the morphology of mitochondria. In this study we have identified a mammalian protein that we call hFis1, which is the orthologue of the yeast Fis1p known to participate in yeast mitochondrial division. hFis1, when overexpressed in various cell types, localized to the outer mitochondrial membrane and induced mitochondrial fission. This event was inhibited by a dominant negative mutant of Drp1 (Drp1(K38A)), a major component of the fission apparatus. Fragmentation of the mitochondrial network by hFis1 was followed by the release of cytochrome c and ultimately apoptosis. Bcl-x L was able to block cytochrome c release and apoptosis but failed to prevent mitochondrial fragmentation. Our studies show that hFis1 is part of the mammalian fission machinery and suggest that regulation of the fission processes might be involved in apoptotic mechanisms.

Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells

“…37 In particular, overexpression of the human fission protein hFis1, an integral protein of the outer mitochondrial membrane, triggers fission of mitochondria, Cyt c release and subsequent apoptosis. 18,38 Furthermore, Bax colocalizes at mitochondrial fission sites early in the apoptotic process, 39 linking proapoptotic members of the Bcl-2 family to the mitochondrial fission and fusion machinery. Thus, we analyzed the presence and the possible interaction of hFis1 with mitochondrial lipid microdomains.…”

Mitochondrial factors with dual roles in death and survival

“…Indeed, human Drp1 was shown to be responsible for the excessive mitochondrial fission/fragmentation that occurs during programmed cell death in mammalian cells (Frank et al, 2001;Breckenridge et al, 2003;James et al, 2003). Furthermore, Drp1 plays an important role in cytochrome c release.…”

“…Thus, it appears that Fis1, found in a protein complex with Dnm1/Drp1, both promotes and limits the action of Dnm1/Drp1. Mammalian Fis1 may have a similar function, though most have reported only its fission function (James et al, 2003;Lee et al, 2004). This dual role of Fis1 is reminiscent of CED-9 that inhibits cell death in worms, but also promotes cell death in a Drp1-dependent manner (Hengartner and Horvitz, 1994b;Jagasia et al, 2005) (Figure 2).…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…In mammalian cells, mitochondrial division is regulated by dynamin related protein 1 (Drp1) and Fis1. 10,11 The large GTPase Drp1 is a cytosolic dynaminrelated protein. Its inhibition or its downregulation result in a highly interconnected mitochondrial network.…”

“…49 Supporting this scenario, the partner of Drp1 on mitochondrial membranes, Fis1, is also a player in apoptosis: its overexpression leads to cytochrome c release, while its ablation protects from cell death. 11,51 Furthermore, fragmentation is the only known and essential involvement of mitochondria during developmental apoptosis of Caenorhabditis elegans. 52 Not only the pro-fission proteins are activated during apoptosis, but Mfn1-dependent fusion is impaired, as elegantly shown by Karbowski, Youle, and colleagues.…”