June 2015
Volume 56, Issue 7
ARVO Annual Meeting Abstract  |   June 2015
Mitochondrial damage and the role of TGF-β in keratoconus
Author Affiliations & Notes
  • Dimitrios Karamichos
    Ophthalmology, OUHSC, Dean McGee Eye Institute, Oklahoma City, OK
    Cell Biology, OUHSC, Oklahoma City, OK
  • Akhee Sarker-Nag
    Ophthalmology, OUHSC, Dean McGee Eye Institute, Oklahoma City, OK
  • Footnotes
    Commercial Relationships Dimitrios Karamichos, None; Akhee Sarker-Nag, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2041. doi:
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      Dimitrios Karamichos, Akhee Sarker-Nag; Mitochondrial damage and the role of TGF-β in keratoconus. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2041.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Keratoconus (KC) is a complex corneal dystrophy with multifactorial etiology. Previous genetic studies have demonstrated evidence of mitochondrial abnormalities in KC. While efforts have been made over the years, the exact cause of the mitochondrial abnormalities in these individuals remains unknown. Transforming growth factor-β (TGF-β) and its role in KC mitochondrial regulation is unknown. The aim of this study was to identify regulation of mitochondrial proteins on human keratoconus cells and the role of TGF-β isoforms.

Methods: Human corneal fibroblasts (HCF) and Human keratoconus cells (HKC) were isolated and cultured. Cells were cultured for four weeks in three different conditions: a) Controls: MEM+10%FBS, b) MEM+10%FBS+TGF-β1 (0.1ng/ml), and MEM+10%FBS+TGF-β3 (0.1ng/ml). All samples were processed for mitochondrial damage analysis using real-time PCR and western blots.

Results: We identified a total of 96 mitochondrial proteins of which >15 were significantly different between normal and KC corneal cells. More than 30 proteins were further modulated upon TGF-β1 or TGF-β3 stimulation. The solute carrier (SLC) groups of membrane transport proteins were highly affected in KC cells. Particularly the SLC25 family had multiple isoforms regulated such as A2, A4, A23, and A27 were all significantly up regulated in HKCs (p<0.05). On the other hand isoforms A21 and A24 were significantly down regulated in HKCs when compared to HCFs (p<0.05). SLC25 is family known for its role as mitochondrial carrier and responsible for basic functions such as phosphorylation and redox state. TGF-β1 stimulation led to massive up regulation of mitofusin-1, a facilitator of mitochondrial targeting, in HKCs when compared to HCFs (180 fold; p<0.05). SLC25A31 was down regulated (14 fold) as well as isoform A37, following TGF-β1 stimulation. TGF-β3 stimulation led to a 14 fold up regulation of isoform A27 in HKCs and a 3 fold down regulation of superoxide dismutase 2 (SOD2), often associated with neuron diseases, cancer and ocular anti-oxidative capacity.

Conclusions: Overall, our data supports the growing consensus that mitochondrial dysfunction is a key player in KC disease. These in vitro data shows clear links between mitochondrial function and TGF-β isoforms. TGF-β1 seems to severely disrupt KC mitochondrial function while TGF-β3 maintained it. These data also suggest that TGF-β3 may play a role in KC disease treatment.


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