Increased Mobile Zinc Regulates Retinal Ganglion Cell Survival via Activating Mitochondrial OMA1 and Integrated Stress Response

Abstract

Retinal ganglion cells (RGCs), the projection neurons of the eye, are irreversibly lost once the optic nerve is injured, which is a critical mechanism of glaucoma. Mobile zinc (Zn2+) levels rapidly increase in retinal interneuron amacrine cells and Zn2+ is then transferred to RGCs via the Zn2+ transporter protein ZnT-3, triggering RGC loss in optic nerve injury. Zn2+ chelation and ZnT-3 deletion promote long-term RGC survival. However, the downstream signaling pathways of Zn2+ in RGCs remains unknown. Here, we show that increased levels of Zn2+ upregulate the expression and activity of mitochondrial zinc metallopeptidase OMA1 in the retina, leading to the cleavage of DELE1 and activation of cytosolic eIF2α kinase PKR, triggering the integrated stress response (ISR) in RGCs. Our study identified OMA1 and ISR as the downstream molecular mechanisms of retinal Zn2+ and potential targets for preventing the progression of Zn2+-associated neuronal damage.

The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro

“…Contrary to our expectations, the results of our study did not demonstrate any modulation of Ca 2+ -induced mitochondrial swelling by Myls22. Likewise, TPEN, a zinc-chelator and OMA1 inhibitor [ 17 , 38 ], was not effective in preventing Ca 2+ -induced mitochondrial swelling. It is tempting to speculate that OPA1 oligomerization can be more essential for maintaining the mitochondrial cristae structure than OPA1 cleavage as demonstrated by the genetically modified MEFs, which were able to maintain a moderate cristae structure with only S-OPA1 expression [ 9 ].…”

“…Recent studies have demonstrated that the inhibition of OPA1 GTPase activity by Myls22 is protective against breast cancer growth [ 16 ]. Similarly, inhibition of OMA1 by N,N,N’,N’-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) reduced mitochondrial damage induced by optic nerve injury in C57BL/6J mice [ 17 ], suggesting beneficial effects of L-OPA1 under stress conditions. It is important to mention, however, that TPEN’s ability to chelate zinc may have unspecific impacts on mitochondria.…”

Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes

“…We have previously shown that Ca 2+ -induced mitochondrial swelling stimulates proteolytic cleavage of L-OPA1 in isolated cardiac mitochondria [ 63 ]. Recently, Myls22, an OPA1 inhibitor, and TPEN (N, N, N’, N’-tetrakis(2-pyridylmethyl) ethylenediamine), a Zn 2+ -chelator and OMA1 inhibitor [ 64 ], exhibited protective effects against breast cancer growth [ 65 ] and attenuated mitochondrial damage [ 66 ]. Despite these promising effects, the role of OPA1 and OMA1 inhibition under Ca 2+ -induced mitochondrial swelling is yet to be evaluated.…”

Loss of UCP2 causes mitochondrial fragmentation by OMA1‐dependent proteolytic processing of OPA1 in podocytes

“…16 OMA1 in the mitochondrial inner membrane is involved in the proteolysis and downregulation of OPA1 during stress and apoptosis. [17][18][19][20] The mitochondrial inner membrane uncoupling protein, UCP2, is extensively distributed in the spleen, pancreas, heart, lungs, brain, muscles, and kidneys, 21 and it has a high homology with UCP1. Its main function was previously considered to be proton transport from the mitochondrial intermembrane space to the mitochondrial matrix as well as reducing ATP synthesis, but subsequent studies found that UCP2 is involved in regulating fatty acid metabolism, mitochondrial calcium ion transport, and reactive oxygen species (ROS) production.…”

“…The mitochondrial inner membrane zinc metalloprotease, OMA1, and the i‐AAA protease, YME1L, are involved in OPA1 processing 16 . OMA1 in the mitochondrial inner membrane is involved in the proteolysis and downregulation of OPA1 during stress and apoptosis 17–20 …”