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All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

ABSTRACT: Hydrogen peroxide (H₂O₂) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H₂O₂ biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H₂O₂ demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H₂O₂ diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H₂O₂ between mitochondrial compartments provide a map of mitochondrial H₂O₂ diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.

SUBMITTER: Koren SA

PROVIDER: S-EPMC10533892 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

Koren Shon A SA Ahmed Selim Nada N De la Rosa Lizbeth L Horn Jacob J Farooqi M Arsalan MA Wei Alicia Y AY Müller-Eigner Annika A Emerson Jacen J Johnson Gail V W GVW Wojtovich Andrew P AP

Nature communications 20230927 1

Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS- ...[more]

PMID: 37758713

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Project description:Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not known if these channels regulate the spatiotemporal spread of signaling microdomains. Here, we employed a multiscale, morphologically realistic, conductance-based model of the hippocampal pyramidal neuron that accounted for experimental details of electrical and calcium-dependent biochemical signaling. We activated synaptic N-Methyl-d-Aspartate receptors through theta-burst stimulation (TBS) or pairing (TBP) and assessed microdomain propagation along a signaling pathway that included calmodulin, calcium/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1. We found that the spatiotemporal spread of the TBS-evoked microdomain in phosphorylated CaMKII (pCaMKII) was amplified in comparison to that of the corresponding calcium microdomain. Next, we assessed the role of two dendritically expressed inactivating channels, one restorative (A-type potassium) and another regenerative (T-type calcium), by systematically varying their conductances. Whereas A-type potassium channels suppressed the spread of pCaMKII microdomains by altering the voltage response to TBS, T-type calcium channels enhanced this spread by modulating TBS-induced calcium influx without changing the voltage. Finally, we explored cross-dependencies of these channels with other model components, and demonstrated the heavy mutual interdependence of several biophysical and biochemical properties in regulating microdomains and their spread. Our conclusions unveil a pivotal role for dendritic voltage-gated ion channels in actively amplifying or suppressing biochemical signals and their spatiotemporal spread, with critical implications for clustered synaptic plasticity, robust information transfer and efficient neural coding.

Dataset Information

All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

Publications

All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.

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