Mitofusin 1 is degraded at G2/M phase through ubiquitylation by MARCH5

Here, we report that mitochondria were found to be fragmented in G2 phase prior to mitotic entry. Mitofusin 1 (Mfn1), a mitochondrial fusion protein, interacted with cyclin B1, and their interactions became stronger in G2/M phase. In addition, MARCH5, a mitochondrial E3 ubiquitin ligase, reduced Mfn1 levels and the MARCH5-mediated Mfn1 ubiquitylation were enhanced in G2/M phase.Mfn1 is degraded through the MARCH5-mediated ubiquitylation in G2/M phase and the cell cycle-dependent degradation of Mfn1 could be facilitated by interaction with cyclin B1/Cdk1 complexes.Mitochondria are multifunctional organelles that play essential roles in many cellular functions, including respiration, ATP production, and calcium buffering [1,2]. In most cell types, mitochondria form a tubular network structure whose morphology changes dynamically through a controlled balance of fusion and fission events. Mitofusins (Mfn1/2) and Opa1 (optic atrophy 1) are essential for the fusion of mitochondrial outer and inner membranes, respectively. Drp1 (dynamin related protein 1) has pivotal roles in fission events through association with Fis1 (fission 1) or Mff [3,4]. An imbalance in mitochondrial dynamics affects cellular physiology. For example, abnormally elongated mitochondria, caused by depletion of Fis1 or MARCH5, induce cellular senescence [5,6]. Moreover, extensive mitochondrial fragmentation is observed in apoptotic cells, whereas cells with elongated mitochondria are more resistant to apoptotic stimuli [7,8].Mitochondrial biogenesis and function are integrated with the nuclear cell cycle. Diminished production of ATP caused by mutations in the mitochondrial protein, tenured (tend), which encodes a cytochrome oxidase subunit Va, causes G1/S cell-cycle arrest during larval growth in Drosophila[9]. Mitochondrial function is also affected by p53 [10]. Additionally, mitochondria are known to show dynamic morphology during cell-cycle stages [11-13]. Cyclin D1, a G1/S-phase controlling protei