Novel Role of Mitochondrial Matrix Metalloproteinase-2 in the Development of Diabetic Retinopathy
Open Access
- 1 May 2011
- journal article
- research article
- Published by Association for Research in Vision and Ophthalmology (ARVO) in Investigative Ophthalmology & Visual Science
- Vol. 52 (6), 3832-3841
- https://doi.org/10.1167/iovs.10-6368
Abstract
Purpose.: In the pathogenesis of diabetic retinopathy, retinal mitochondria become dysfunctional, their DNA is damaged, and capillary cells undergo accelerated apoptosis. Matrix metalloproteinase-2 (MMP2) becomes activated and proapoptotic, and the therapies that inhibit the development of diabetic retinopathy alleviate MMP2 activation. The authors sought to elucidate the possible mechanism by which activated MMP2 contributes to mitochondrial dysfunction. Methods.: The effect of the regulation of MMP2 on mitochondrial dysfunction and the subcellular localization of the molecular chaperone important for mitochondrial integrity (Hsp60) and gap junction protein connexin 43 were investigated in retinal endothelial cells. The results were confirmed in retinal mitochondria isolated from diabetic mouse overexpressing MnSOD and in the retinas of normal rats that received intravitreal administration of MMP2. Results.: High glucose increased MMP2 and decreased connexin 43 in the mitochondria of retinal endothelial cells. Although the Hsp60 gene transcript was increased, its abundance in the mitochondria was decreased, and its interaction with MMP2 was increased. In mice, the overexpression of MnSOD protected retinal mitochondria from diabetes-induced increases in MMP2 and decreases in Hsp60 and connexin 43. MMP2 administration in normal rats damaged the retinal mitochondria, decreased Hsp60 and connexin 43, and accelerated the apoptosis of retinal capillary cells. Conclusions.: Elevated MMP2 in the mitochondria degrades its membranes by modulating Hsp60 and damaging connexin 43, and this activates the apoptotic machinery. Better understanding of MMP2-mediated mitochondrial damage could help identify new strategies for the treatment of this blinding disease.This publication has 39 references indexed in Scilit:
- The Pathobiology of Diabetic ComplicationsDiabetes, 2005
- Role of Interleukin-1β in the Development of Retinopathy in Rats: Effect of AntioxidantsInvestigative Ophthalmology & Visual Science, 2004
- Reversal of hyperglycemia and diabetic nephropathy: Effect of reinstitution of good metabolic control on oxidative stress in the kidney of diabetic ratsJournal of Diabetes and its Complications, 2004
- Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosisThe EMBO Journal, 1999
- Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin.JCI Insight, 1998
- The ins and outs of a molecular chaperone machineTrends in Biochemical Sciences, 1998
- Simultaneous Overexpression of Two Stress Proteins in Rat Cardiomyocytes and Myogenic Cells Confers Protection Against Ischemia-Induced InjuryCirculation, 1997
- Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy.JCI Insight, 1996
- Programmed Cell Death and the Control of Cell Survival: Lessons from the Nervous SystemScience, 1993
- Vascular heat shock protein expression in response to stress. Endocrine and autonomic regulation of this age-dependent response.JCI Insight, 1993