Journal
NATURE MEDICINE
Volume 20, Issue 5, Pages 559-122Publisher
NATURE RESEARCH
DOI: 10.1038/nm.3520
Keywords
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [Sonderforschungsbereich 870, Transregio 128]
- German Federal Ministry of Research and Education (BMBF, Competence Network Multiple Sclerosis)
- European Research Council (ERC) under the European Union's Seventh Framework Program (FP/ERC) [310932]
- Hertie Foundation
- Verein Therapieforschung fur MS-Kranke e.V
- Institute of Advanced Studies (Technische Universitat Munchen)
- Alexander von Humboldt Foundation
- Center for Integrated Protein Science (Munich) [EXC 114]
- DFG [SFB 596, SFB 870, SFB 938, SFB 1036]
- DZNE (Munich)
- SyNergy [EXC 1010]
- DFG Priority Program 1710
- US National Institutes of Health [Ca 049797]
- Edward P. Evans Foundation
- BMBF ('LungSys')
- Gertrud Reemtsma Foundation (Max Planck Society)
- German National Academic Foundation
- Wings of Life Foundation
- Human Frontier Science Program
- Graduate School of Technische Universitat Munchen
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Mitochondrial redox signals have a central role in neuronal physiology and disease. Here we describe a new optical approach to measure fast redox signals with single-organelle resolution in living mice that express genetically encoded redox biosensors in their neuronal mitochondria. Moreover, we demonstrate how parallel measurements with several biosensors can integrate these redox signals into a comprehensive characterization of mitochondrial function. This approach revealed that axonal mitochondria undergo spontaneous 'contractions' that are accompanied by reversible redox changes. These contractions are amplified by neuronal activity and acute or chronic neuronal insults. Multiparametric imaging reveals that contractions constitute respiratory chain-dependent episodes of depolarization coinciding with matrix alkalinization, followed by uncoupling. In contrast, permanent mitochondrial damage after spinal cord injury depends on calcium influx and mitochondrial permeability transition. Thus, our approach allows us to identify heterogeneity among physiological and pathological redox signals, correlate such signals to functional and structural organelle dynamics and dissect the underlying mechanisms.
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