Mitofusin-2-mediated tethering of mitochondria and endoplasmic reticulum promotes cell cycle arrest of vascular smooth muscle cells in G0/G1 phase.
Mitofusin-2 (Mfn-2) is a hyperplasia suppressor. Changes in Mfn-2 expression are thought to reflect mitochondrial remodeling during cell proliferation. However, it is unclear how the participation of Mfn-2 in mitochondrial remodeling prevents cellular proliferation. Here we show that arresting vascular smooth muscle cells (VSMCs) in the G0/G1 phase by serum starvation up-regulates Mfn-2 expression and causes mitochondria to assemble into a tubular network and to attach to the endoplasmic reticulum (ER). In the S phase, short rod-shaped mitochondrial structures that were dissociated from the ER were observed. Levels of glucose, ATP, l-amino acid, and NADP(+) did not vary throughout the cell cycle. However, NAD(+) level was lower and NADH level was higher in the G0/G1 phase than in the S phase. Mitochondrial membrane potential was lower in the S phase than in the G0/G1 phase. Infecting VSMCs with an adenovirus encoding full-length Mfn-2 increased NADH level and reduced NAD(+) level, while infecting the cells with an adenovirus that silences the p21(ras) signature motif produced opposite effects. These results suggest that Mfn-2 up-regulation causes mitochondrial fusion into tubular networks and attachment to the ER, which in turn halts proliferation of VSMCs.
Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China lidan2014@tjh.tjmu.edu.cn xmguo@tjh.tjmu.edu.cn.
Dan
D
Li
Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Xiaolan
X
Li
Department of Ultrastructural Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Yang
Y
Guan
Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China lidan2014@tjh.tjmu.edu.cn xmguo@tjh.tjmu.edu.cn.
Xiaomei
X
Guo
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000502:physiology*; D016193:G1 Phase; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009243:NAD / Q000096:biosynthesis; D051381:Rats; D011921:Rats, Inbred WKY; D016192:Resting Phase, Cell Cycle
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009243:NAD; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
cell cycle arrest; endoplasmic reticulum; mitochondria; mitofusin-2; vascular smooth muscle cells