Mitochondrial ferritin affects mitochondria by stabilizing HIF-1α in retinal pigment epithelium: implications for the pathophysiology of age-related macular degeneration.
Mitochondrial ferritin (FtMt) is believed to play an antioxidant role via iron regulation, and FtMt gene mutation has been reported in age-related macular degeneration (AMD). However, little is known about FtMt's functions in the retina and any links to AMD. In this study, we observed age-related increase in FtMt and hypoxia-inducible factor-1α (HIF-1α) in murine retinal pigment epithelium (RPE). FtMt overexpression in ARPE-19 cells stabilized HIF-1α, and increased the secretion of vascular endothelial growth factor. Conversely, HIF-1α stabilization reduced the protein level of the mature, functional form of FtMt. FtMt-overexpressing ARPE-19 cells exhibited less oxidative phosphorylation but unchanged production of adenosine triphosphate, enhanced mitochondrial fission, and triggered mitophagy in a HIF-1α-dependent manner. These findings suggest that increased FtMt in RPE may be protective via triggering mitophagy but cause wet AMD by inducing neovascularization due to increased vascular endothelial growth factor secretion. However, reduced level of functional FtMt in RPE under hypoxia may allow dry AMD through susceptibility to age-related stress.
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, P.R. China.
Xiying
X
Wang
Department of Neurosurgery, First Affiliated Hospital, Harbin Medical University, Harbin, P.R. China; Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu Japan.
Hongkuan
H
Yang
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu Japan.
Daijiro
D
Yanagisawa
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu Japan.
Jean-Pierre
JP
Bellier
Department of Internal Medicine, Shiga University of Medical Science, Otsu Japan.
Katsutaro
K
Morino
Department of Neurosurgery, First Affiliated Hospital, Harbin Medical University, Harbin, P.R. China.
Shiguang
S
Zhao
Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, P.R. China. Electronic address: pingliu53@126.com.
Ping
P
Liu
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu Japan.
Piers
P
Vigers
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu Japan. Electronic address: kinchan@belle.shiga-med.ac.jp.
Ikuo
I
Tooyama
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants; D002478:Cells, Cultured; D005293:Ferritins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology*; D063154:Mitochondrial Dynamics; D063306:Mitophagy; D009154:Mutation; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000975:Antioxidants; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000255:Adenosine Triphosphate; D005293:Ferritins; D007501:Iron
Age-related macular degeneration; HIF-1α; Mitochondria; Mitochondrial ferritin; Neurodegeneration