The Novel Tail-anchored Membrane Protein Mff Controls Mitochondrial and Peroxisomal Fission in Mammalian Cells

Abstract

Few components of the mitochondrial fission machinery are known, even though mitochondrial fission is a complex process of vital importance for cell growth and survival. Here, we describe a novel protein that controls mitochondrial fission. This protein was identified in a small interfering RNA (siRNA) screen using Drosophila cells. The human homologue of this protein was named Mitochondrial fission factor (Mff). Mitochondria of cells transfected with Mff siRNA form a closed network similar to the mitochondrial networks formed when cells are transfected with siRNA for two established fission proteins, Drp1 and Fis1. Like Drp1 and Fis1 siRNA, Mff siRNA also inhibits fission induced by loss of mitochondrial membrane potential, it delays cytochrome c release from mitochondria and further progression of apoptosis, and it inhibits peroxisomal fission. Mff and Fis1 are both tail anchored in the mitochondrial outer membrane, but other parts of these proteins are very different and they exist in separate 200-kDa complexes, suggesting that they play different roles in the fission process. We conclude that Mff is a novel component of a conserved membrane fission pathway used for constitutive and induced fission of mitochondria and peroxisomes.

The mitochondrial dynamics in cancer and immune-surveillance

“…In addition, while in healthy cells soluble Bax can promote mitochondrial fusion by favouring Mfn-2 complex assembly [48], membrane-bound Bax can inhibit Mfn-2 activity during apoptosis, thus favouring, instead, Drp1-driven mitochondrial hemi-fission. The prevention of mitochondrial fission has normally an anti-apoptotic effect: Bcl-X L performs part of its anti-apoptotic activity by inhibiting Drp1 [49], and the down-regulation of pro-fission Mff has a considerable anti-apoptotic effect [36]. However, Mfn-1 KO MEFs are resistant to apoptotic stimuli.…”

“…Genetic ablation of Drp1 is embryonically lethal in mice because of abnormal neuronal development [32]. Drp1 does not act alone, but different "accomplices" assist Drp1-docking at OMMs: Fis1, the role of which is still controversial in mammals [33,34]; Mff [35,36]; MiD51 and MiD49 [37]. In addition, other "less conventional" proteins can mediate Drp1 recruitment at OMM, and promote mitochondria fission, such as the cytoplasmic kinase leucine-rich-repeat kinase 2 (LRRK2) [38,39], the membrane trafficking and apoptosis regulator small Ras family member G-protein Rab32 [40,41] and the very recently discovered dynamin-2 (Dyn-2) [42].…”

Miro1 – the missing link to peroxisome motility

“…This targeting appears to be largely dependent on the biochemical properties of their C-terminal amino acid sequence (principally the hydrophobicity of the TMD and the net charge in the tail region) and, as such, it can be characterized and used to predict the targeting of TA proteins [12]. Interestingly, Miro1 has an identical TMD hydrophobicity and tail charge to that of Mff, another dually targeted protein involved in mitochondrial and peroxisomal division [24]. …”

Charcot‐Marie‐Tooth disease‐associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission

“…Next, the membrane of the elongated peroxisome forms constrictions by a not yet clearly defined mechanism [6]. Final fragmentation requires several fission proteins, including the tail-anchored (TA) proteins hFis1 (fission 1), Mff (mitochondrial fission factor) and the cytosolic Drp1/DLP1 (dynamin-related protein 1) [7][8][9][10][11][12]. These proteins are also essential fission factors at the mitochondrial outer membrane (MOM).…”