Short Variant of Mitochondrial Dynamin OPA1 Renders Improved Cell Survival under Stress Conditions

Abstract

The protein optic atrophy 1 (OPA1) is a dynamin‐related membrane remodeling protein associated with the inner mitochondrial membrane. OPA1 is a critical factor for mitochondrial structure and function by mediating mitochondrial inner membrane fusion and maintaining cristae structure. Under cellular stress associated with mitochondrial dysfunction, the inner membrane‐anchored long OPA1 (L‐OPA1) undergoes proteolytic cleavage to form short soluble OPA1 (S‐OPA1) lacking the transmembrane domain. The prevalent thought has been that S‐OPA1 is a functionally insignificant proteolytic product of L‐OPA1. Hence, the loss of L‐OPA1 and accumulation of S‐OPA1 by OPA1 cleavage under stress conditions is thought to be detrimental to cell survival. However, we recently demonstrated that S‐OPA1 is fully competent for maintaining energetics and cristae structure. Therefore, in this study, we used cells exclusively expressing L‐, S‐OPA1, or both, and tested the capacity of L‐ and S‐OPA1 in supporting cell survival under stress conditions. Under hydrogen peroxide‐mediated oxidant stress, we found that S‐OPA1‐expressing cells have better survival than L‐OPA1 cells. Interestingly, this difference in cell survival under oxidant stress was only observed in glucose‐free OXPHOS media but not in the presence of glucose, suggesting that S‐OPA1 may confer higher mitochondrial energetic activity compared with L‐OPA1. We also observed better survival of S‐OPA1‐expressing cells under nutrient starvation. Under apoptotic stress by treating cells with the transcription inhibitor actinomycin D, S‐OPA1 cells showed greatly decreased cytochrome c release compared to L‐OPA1 cells. These observations suggest that S‐OPA1 is more protective during apoptosis than L‐OPA1. Mechanistically, we found that S‐OPA1 cells have higher mitochondrial electron transport activity in nutrient depletion. Furthermore, by testing mitochondrial calcium retention capacity, we found that S‐OPA1 cells show increased resistance to mitochondrial permeability transition induced by mitochondrial calcium overload, compared with L‐OPA1 only cells. These data indicate that S‐OPA1 confers more efficient energy metabolism and more resistance to mitochondrial stress, allowing prolonged cell survival under stress.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.