Therapeutic potential of PGC-1α in age-related macular degeneration (AMD) – the involvement of mitochondrial quality control, autophagy, and antioxidant response

ABSTRACT

Introduction

Age-related macular degeneration (AMD) is the leading, cause of sight loss in the elderly in the Western world. Most patients remain still without any treatment options. The targeting of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a transcription co-factor, is a putative therapy against AMD.

Areas covered

The characteristics of AMD and their possible connection with PGC-1α as well as the transcriptional and post-transcriptional control of PGC-1α are discussed. The PGC-1α-driven control of mitochondrial functions, and its involvement in autophagy and antioxidant responses are also examined. Therapeutic possibilities via drugs and epigenetic approaches to enhance PGC-1α expression are discussed. Authors conducted a search of literature mainly from the recent decade from the PubMed database.

Expert opinion

Therapy options in AMD could include PGC-1α activation or stabilization. This could be achieved by a direct elevation of PGC-1α activity, a stabilization or modification of its upstream activators and inhibitors by chemical compounds, like 5-Aminoimidazole-4-carboxamide riboside, metformin, and resveratrol. Furthermore, manipulations with epigenetic modifiers of PGC-1α expression, including miRNAs, e.g. miR-204, are considered. A therapy aimed at PGC-1α up-regulation may be possible in other disorders besides AMD, if they are associated with disturbances in the mitochondria-antioxidant response-autophagy axis.

KEYWORDS:

• Age-related macular degeneration
• antioxidant response
• autophagy
• mitochondria
• pgc-1α
• retinal pigment epithelium

Funding

We are grateful to our supporters: the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722717, the of Finland (296840, 333302), the Kuopio University Hospital VTR grant (5503770), the Sigrid Juselius Foundation, the Päivikki and Sakari Sohlberg Foundation, the University of Eastern Finland strategical support, the Finnish Eye Foundation and National Science Centre, Poland (2017/27/B/NZ3/00872).

Acknowledgments

The authors appreciate warmly Dr. Ewen MacDonald for the revision of the English language.

Author contribution

J.M.T.H.: conceptualization, writing - original draft, writing - revision and editing, visualization. J.B.: writing - revision. P.T.: writing - revision. K.K.: conceptualization, writing - revision, supervision.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Article Highlights

• Mitochondrial dysfunction, decline of autophagic clearance and weakening of antioxidant responses are considered to be important aspects in the pathogenesis of AMD.

• PGC-1α improves cellular energy metabolism, clearance and prevents degenerative processes.

• Because of the positive effects of PGC-1α on mitochondria function, protein clearance and antioxidant production it is a potential therapeutic target in AMD.

• The possible therapeutic approaches include pharmacological treatments and epigenetic manipulation of PGC-1α expression with microRNAs.