Abstract
Mitochondrial oxidative phosphorylation (OXPHOS) defects are the primary cause of inborn errors of energy metabolism. Despite considerable progress on their genetic basis, their global pathophysiological consequences remain undefined. Previous studies reported that OXPHOS dysfunction associated with complex III deficiency exacerbated the expression and mitochondrial location of cytoskeletal gelsolin (GSN) to promote cell survival responses. In humans, besides the cytosolic isoform, GSN presents a plasma isoform secreted to extracellular environments. We analyzed the interplay between both GSN isoforms in human cellular and clinical models of OXPHOS dysfunction. Regardless of its pathogenic origin, OXPHOS dysfunction induced the physiological upregulation of cytosolic GSN in the mitochondria (mGSN), in parallel with a significant downregulation of plasma GSN (pGSN) levels. Consequently, significantly high mGSN-to-pGSN ratios were associated with OXPHOS deficiency both in human cells and blood. In contrast, control cells subjected to hydrogen peroxide or staurosporine treatments showed no correlation between oxidative stress or cell death induction and the altered levels and subcellular location of GSN isoforms, suggesting their specificity for OXPHOS dysfunction. In conclusion, a high mitochondrial-to-plasma GSN ratio represents a useful cellular indicator of OXPHOS defects, with potential use for future research of a wide range of clinical conditions with mitochondrial involvement.
Highlights
Mitochondria participate in a large variety of metabolic and physiological processes, such as lipid metabolism, iron-sulphur cluster biogenesis, hormone and reactive oxygen species (ROS)signaling, calcium buffering, and apoptosis, and importantly, they provide most of the energy (ATP)usable by cells through the oxidative phosphorylation (OXPHOS) system
Previous studies in mitochondrial complex III (CIII)-deficient cell lines revealed a specific upregulation of cytosolic GSN and its localization to the mitochondrial outer membrane, where it interacts with VDAC1 to promote protective antiapoptotic responses [12,40]
This can be extremely helpful, for instance, to differentiate the impact of specific pathogenic mutations or drug treatments in different cultured cell types originally derived from patients, as well as to select for genetically edited cellular models of mitochondrial disorders (MDs). (5) In addition, we provide a proof of principle for future research on the mitochondrial GSN (mGSN):plasma GSN (pGSN) ratio as a potential diagnostics tool for mitochondrial disease (MD)
Summary
Mitochondria participate in a large variety of metabolic and physiological processes, such as lipid metabolism, iron-sulphur cluster biogenesis, hormone and reactive oxygen species (ROS)signaling, calcium buffering, and apoptosis, and importantly, they provide most of the energy (ATP)usable by cells through the oxidative phosphorylation (OXPHOS) system. Cells 2020, 9, 1922 complexes and two mobile electron carriers (ubiquinone and cytochrome c) that couple respiration to ATP synthesis: Complexes I to IV (CI-CIV) constitute the mitochondrial respiratory chain (MRC), which transfers electrons from NADH and FADH2 to molecular oxygen, with a parallel generation of a proton gradient across the mitochondrial inner membrane that is used by complex V for ATP synthesis [1]. Despite the wide knowledge on the molecular genetic origins of OXPHOS disorders [10], their underlying pathophysiological mechanisms remain mostly unknown. The diagnosis of OXPHOS diseases remains challenging due to their wide clinical heterogeneity, and research for specific and sensitive diagnostic tools based on serum biomarkers is currently active [10]
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