Uncovering the relationship between optic atrophy-1 protein and mitochondria function
PHYSIOLOGY(2023)
Abstract
Mitochondria, known as the powerhouse of the cell, also participate in the regulation of ion homeostasis, redox status, cell growth and differentiation, lipid metabolism, and cell death. The inner mitochondrial membrane (IMM) plays a crucial role in the regulation of mitochondrial metabolism and function. The dynamin-related GTPase optic atrophy-1 (OPA1) localized in the IMM is responsible for mitochondria fusion. In addition, OPA1 has been shown to play an important role in maintaining the structural integrity and functional activity of mitochondrial cristae. We have recently shown that mitochondrial swelling stimulates enzymatic cleavage of OPA1 by OMA1, a zinc metallopeptidase, which converts long-OPA1 (L-OPA1) to short-OPA1 (S-OPA1). Cleavage of L-OPA1 was suggested to diminish mitochondrial fusion and bioenergetics leading to cell death. The role of OPA1 cleavage and OMA1 activation under diverse swelling conditions has not yet been elucidated. In this study, we investigated the role of OPA1 cleavage under various mitochondrial swelling conditions in the presence and absence of Myls22 (an OPA1 inhibitor), and TPEN (a zinc-chelator and OMA1 inhibitor). Cardiac mitochondria were isolated from Sprague Dawley rats and their function was assessed under Ca2+-induced mitochondrial swelling with oxoglutarate and malate (OM) with/without ADP. Our dose-dependent experiments revealed that Myls22 and TPEN exert the maximum effect at 50 and 5 μM, respectively. Next, we found that the maximum respiration rate (state 3) of mitochondria for complex I is diminished by both inhibitors. However, neither Myls22 nor TPEN prevented alterations in mitochondrial respiration rates, swelling, membrane potential, and calcium retention capacity induced by Ca2+. Finally, we evaluated the protein expression of L-OPA1 via western blot and found more OPA1 cleavage under state 3 compared to state 2 respiration rate suggesting the regulatory role of S-OPA1 in mitochondrial respiration. Thus, our data demonstrate that although mitochondrial swelling stimulates L-OPA cleavage associated with mitochondrial dysfunction, inhibition of OPA1 cleavage/OMA1 activity by Mysl22/TPEN is ineffective in ameliorating the effects of Ca2+-induced mitochondria swelling. This study was supported by the National Science Foundation (Grant 2006477). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Key words
protein
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