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Mitochondrial quality control in AMD: does mitophagy play a pivotal role?

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Abstract

Age-related macular degeneration (AMD) is the predominant cause of visual loss in old people in the developed world, whose incidence is increasing. This disease is caused by the decrease in macular function, due to the degeneration of retinal pigment epithelium (RPE) cells. The aged retina is characterised by increased levels of reactive oxygen species (ROS), impaired autophagy, and DNA damage that are linked to AMD pathogenesis. Mitophagy, a mitochondria-specific type of autophagy, is an essential part of mitochondrial quality control, the collective mechanism responsible for this organelle’s homeostasis. The abundance of ROS, DNA damage, and the excessive energy consumption in the ageing retina all contribute to the degeneration of RPE cells and their mitochondria. We discuss the role of mitophagy in the cell and argue that its impairment may play a role in AMD pathogenesis. Thus, mitophagy as a potential therapeutic target in AMD and other degenerative diseases is as well explored.

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Abbreviations

AMBRA1:

Activating molecule in beclin-1-regulated autophagy

AMD:

Age-related macular degeneration

AMPK:

AMP-activated protein kinase

ARE:

Antioxidant-binding element

Atg:

Autophagy-related gene

DMT1:

Divalent metal transporter 1

ER:

Endoplasmic reticulum

FPN1:

Ferroportin 1

FPF:

Flavoprotein fluorescence

FtMt:

Mitochondrial ferritin

Gp78:

Glycoprotein 78

HDAC6:

Histone deacetylase 6

HIF-1α:

Hypoxia-inducible factor-1α

Hsp:

Heat-shock protein

IMM:

Inner mitochondrial membrane

Keap1:

Kelch-like ECH-associated protein 1

LIR:

MAPK1LC3-interacting region

MAM:

Mitochondria-associated endoplasmic reticulum membrane

MAPK:

Mitogen-activated protein kinase

MAPK1LC3:

Microtubule-associated protein 1 light-chain 3

Mfn:

Mitofusin

MMP:

Mitochondrial membrane potential

MPT:

Mitochondrial permeability transition

MRC:

Mitochondrial respiratory chain

mtDNA:

Mitochondrial DNA

mTORC1:

Mammalian target of rapamycin complex 1

Mul1:

Mitochondrial E3 ubiquitin ligase

Nrf2:

Nuclear factor (erythroid-derived 2)-related factor 2

OMM:

Outer mitochondrial membrane

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator-1α

PI3K:

Phosphatidylinosotole-3-kinase

PINK1:

Phosphatase and tensin homologue-induced putative kinase

POS:

Photoreceptor outer segment

ROS:

Reactive oxygen species

RGC:

Retinal ganglion cell

RPE:

Retinal pigment epithelium

SAMD:

Senescence-associated mitochondrial dysfunction

SASP:

Senescent-associated secretory phenotype

Sirt1:

NAD-dependent deacetylase Sirtuin 1

Smurf1:

SMAD-specific E3 ubiquitin protein ligase 1

SOD:

Superoxide dismutase

SQSTM1/p62:

Sequestosome1/p62

Tfam:

Mitochondrial transcription factor A

TIM:

Translocase of the inner mitochondrial membrane

TOM:

Translocase of the outer mitochondrial membrane

Ub:

Ubiquitin

VDAC:

Voltage-dependent anion channel

VEGF:

Vascular endothelial growth factor

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The authors thank Mr. Thomas Dunlop for checking the language of the manuscript.

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Authors and Affiliations

  1. Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Juha M. T. Hyttinen, Johanna Viiri & Kai Kaarniranta

  2. Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, 70029 KYS, Kuopio, Finland

    Kai Kaarniranta

  3. Department of Molecular Genetics, University of Łódź, Pomorska 141/143, 90-236, Łódź, Poland

    Janusz Błasiak

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  1. Juha M. T. Hyttinen
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Correspondence to Juha M. T. Hyttinen.

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Hyttinen, J.M.T., Viiri, J., Kaarniranta, K. et al. Mitochondrial quality control in AMD: does mitophagy play a pivotal role?. Cell. Mol. Life Sci. 75, 2991–3008 (2018). https://doi.org/10.1007/s00018-018-2843-7

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