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Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

  • Published:
Journal of Ocular Biology, Diseases, and Informatics

Abstract

Impairment of mitochondria function and cellular antioxidant systems are linked to aging and neurodegenerative diseases. In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment that contributes to age-related visual dysfunction. Here, we examined changes in mitochondrial function in human RPE cells and sensitivity to oxidative stress with increased chronological age. Primary RPE cells from young (9–20)-, mid-age (48–60)-, and >60 (62–76)-year-old donors were grown to confluency and examined by electron microscopy and flow cytometry using several mitochondrial functional assessment tools. Susceptibility of RPE cells to H2O2 toxicity was determined by lactate dehydrogenase and cytochrome c release, as well as propidium iodide staining. Reactive oxygen species, cytoplasmic Ca2+ [Ca2+]c, and mitochondrial Ca2+ [Ca2+]m levels were measured using 2′,7′-dichlorodihydrofluorescein diacetate, fluo-3/AM, and Rhod-2/AM, respectively, adenosine triphosphate (ATP) levels were measured by a luciferin/luciferase-based assay and mitochondrial membrane potential (ΔΨm) estimated using 5,5′,6,6′-tetrachloro 1,1′3,3′-tetraethylbenzimid azolocarbocyanine iodide. Expression of mitochondrial and antioxidant genes was determined by real-time polymerase chain reaction. RPE cells show greater sensitivity to oxidative stress, reduction in expression of mitochondrial heat shock protein 70, uncoupling protein 2, and superoxide dismutase 3, and greater expression of superoxide dismutase 2 levels with increased chronological age. Changes in mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity were more prominent in samples obtained from >60 years old compared to mid-age and younger donors. These mitochondria abnormalities correlated with lower ATP levels, reduced ΔΨm, decreased [Ca2+]c, and increased sequestration of [Ca2+]m in cells with advanced aging. Our study provides evidence for mitochondrial decay, bioenergetic deficiency, weakened antioxidant defenses, and increased sensitivity of RPE cells to oxidative stress with advanced aging. Our findings suggest that with increased severity of mitochondrial decay and oxidative stress, RPE function may be altered in some individuals in a way that makes the retina more susceptible to age-related injury.

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Abbreviations

AMD:

Age-related macular degeneration

RPE:

Retinal pigment epithelium

H2-DCF-DA:

2′,7′-Dichlorodihydrofluorescin diacetate

JC-1:

5,5′,6,6′-Tetrachloro 1,1′3,3′-tetraethylbenzimid azolocarbocyanine iodide

MPTP:

Mitochondrial permeability transition pore

ROS:

Reactive oxygen species

ΔΨm:

Mitochondrial membrane potential

ATP:

Adenosine Triphosphate

[Ca2+]c :

Cytoplasmic calcium

[Ca2+]m :

Mitochondrial calcium

mtHSP70:

Mitochondrial heat shock protein 70

SOD:

Superoxide dismutase

UCP2:

Uncoupling protein 2

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Acknowledgments

This work was supported by grants from the Ben Franklin Foundation, PA, USA, the National Basic Research Program of China (no. 2007CB512200), and the National Natural Science Foundation of China (no. 30672275, no. 30400486), NEI Core Grant P30 EY01931, and an unrestricted grant from Research to Prevent Blindness, Inc. to the Medical College of Wisconsin, and by grants from Shaanxi Province Departments of Health (no. 2010D56) and Education (no. 2010JK807), China. The first author received support from the China Scholarship Council.

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Authors and Affiliations

  1. Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Yuan He, Roland L. Myers & Joyce Tombran-Tink

  2. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, Guangzhou, 510060, China

    Yuan He, Jian Ge & Zhi Z. Dong

  3. Department of Ophthalmology, the Second Affiliated Hospital of Xi’an College of Medicine, Xi’an, China

    Yuan He

  4. Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USA

    Janice M. Burke

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  1. Yuan He
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Correspondence to Jian Ge or Joyce Tombran-Tink.

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He, Y., Ge, J., Burke, J.M. et al. Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress. j ocul biol dis inform 3, 92–108 (2010). https://doi.org/10.1007/s12177-011-9061-y

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