Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

Kai Kaarniranta, Hannu Uusitalo, Janusz Blasiak, Szabolcs Felszeghy, Ram Kannan, Anu Kauppinen, Antero Salminen, Debasish Sinha, Deborah Ferrington

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

Original languageEnglish (US)
Article number100858
JournalProgress in Retinal and Eye Research
Volume79
DOIs
StatePublished - Nov 2020

Bibliographical note

Funding Information:
This work was supported by the Kuopio University Hospita l (KK), the Finnish Eye Foundation (KK), The Sigrid Juselius Foundation (KK), the Health Research Council of the Academy of Finland ( AK 297267 , 307341 , 328443 , KK 296840 ), the Päivikki and Sakari Sohlberg Foundation (AK, KK), the National Institutes of Health/National Eye Institute ( R01 EY028554 and EY026012 ), the Lindsay Family Foundation and an anonymous benefactor for AMD research (DAF), National Science Centre, Poland (JB, Grant number 2017/27/B/NZ3/00872 ). RBF/IRRF Catalyst Award for Innovative Research Approaches for AMD (DS) and the Jennifer Salvitti Davis Chair in Ophthalmology (DS). We thank Iswariyaraja Sridevi Gurubaran, Ali Koskela and Johanna Viiri for technical assistance in preparing figures.

Funding Information:
This work was supported by the Kuopio University Hospital (KK), the Finnish Eye Foundation (KK), The Sigrid Juselius Foundation (KK), the Health Research Council of the Academy of Finland (AK 297267, 307341, 328443, KK 296840), the P?ivikki and Sakari Sohlberg Foundation (AK, KK), the National Institutes of Health/National Eye Institute (R01 EY028554 and EY026012), the Lindsay Family Foundation and an anonymous benefactor for AMD research (DAF), National Science Centre, Poland (JB, Grant number 2017/27/B/NZ3/00872). RBF/IRRF Catalyst Award for Innovative Research Approaches for AMD (DS) and the Jennifer Salvitti Davis Chair in Ophthalmology (DS). We thank Iswariyaraja Sridevi Gurubaran, Ali Koskela and Johanna Viiri for technical assistance in preparing figures.

Publisher Copyright:
© 2020 The Authors

Keywords

  • Age-related macular degeneration
  • Aggregation
  • Aging
  • Autophagy
  • Clearance
  • Degeneration
  • Mitochondria
  • Mitophagy
  • Retina
  • Retinal pigment epithelium

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